Publications by authors named "Rubén López-Vales"

55 Publications

Microglia Stimulation by Protein Extract of Injured Rat Spinal Cord. A Novel Model for Studying Activated Microglia.

Front Mol Neurosci 2021 20;14:582497. Epub 2021 May 20.

Group of Neuroplasticity and Regeneration, Department of Cell Biology, Physiology and Immunology, Institute of Neurosciences, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Universitat Autònoma de Barcelona, Red de Terapia Celular (TerCel), Bellaterra, Spain.

Research on microglia has established the differentiation between the so-called M1 and M2 phenotypes. However, new frameworks have been proposed attempting to discern between meaningful microglia profiles. We have set up an microglial activation model by adding an injured spinal cord (SCI) lysate to microglial cultures, obtained from postnatal rats, in order to mimic the environment of the spinal cord after injury. We found that under the presence of the SCI lysate microglial cells changed their phenotype, developing less ramified but longer processes, and proliferated. The SCI lysate also led to upregulation of pro-inflammatory cytokines, such as IL-1β, IL-6, and TNF-α, downregulation of the anti-inflammatory cytokines IL-10 and IL-4, and a biphasic profile of iNOS. In addition, a latex beads phagocytosis assay revealed the SCI lysate stimulated the phagocytic capacity of microglia. Flow cytometry analysis indicated that microglial cells showed a pro-inflammatory profile in the presence of SCI lysate. Finally, characterization of the microglial activation in the spinal cord on day 7 after contusion injury, we showed that these cells have a pro-inflammatory phenotype. Overall, these results indicate that the use of SCI lysates could be a useful tool to skew microglia towards a closer phenotype to that observed after the spinal cord contusion injury than the use of LPS or IFNγ.
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http://dx.doi.org/10.3389/fnmol.2021.582497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8176957PMC
May 2021

Bioactive Lipid Mediators in the Initiation and Resolution of Inflammation after Spinal Cord Injury.

Neuroscience 2021 07 2;466:273-297. Epub 2021 May 2.

Departament de Biologia Cellular, Fisiologia i Inmunologia, Institut de Neurociències, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Universitat Autònoma de Barcelona, 08193 Bellaterra, Catalonia, Spain.

Neuroinflammation is a prominent feature of the response to CNS trauma. It is also an important hallmark of various neurodegenerative diseases in which inflammation contributes to the progression of pathology. Inflammation in the CNS can contribute to secondary damage and is therefore an excellent therapeutic target for a range of neurological conditions. Inflammation in the nervous system is complex and varies in its fine details in different conditions. It involves a wide variety of secreted factors such as chemokines and cytokines, cell adhesion molecules, and different cell types that include resident cell of the CNS, as well as immune cells recruited from the peripheral circulation. Added to this complexity is the fact that some aspects of inflammation are beneficial, while other aspects can induce secondary damage in the acute, subacute and chronic phases. Understanding these aspects of the inflammatory profile is essential for developing effective therapies. Bioactive lipids constitute a large group of molecules that modulate the initiation and the resolution of inflammation. Dysregulation of these bioactive lipid pathways can lead to excessive acute inflammation, and failure to resolve this by specialized pro-resolution lipid mediators can lead to the development of chronic inflammation. The focus of this review is to discuss the effects of bioactive lipids in spinal cord trauma and their potential for therapies.
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http://dx.doi.org/10.1016/j.neuroscience.2021.04.026DOI Listing
July 2021

Dual Role of Lysophosphatidic Acid Receptor 2 (LPA) in Amyotrophic Lateral Sclerosis.

Front Cell Neurosci 2021 25;15:600872. Epub 2021 Mar 25.

Departament de Biologia Cellular, Fisiologia i Immunologia, Institut de Neurociències, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Universitat Autònoma de Barcelona, Bellaterra, Spain.

Lysophosphatidic acid (LPA) is a pleiotropic extracellular lipid mediator with many physiological functions that signal through six known G protein-coupled receptors (LPA). In the central nervous system (CNS), LPA mediates a wide range of effects including neural progenitor cell physiology, neuronal cell death, axonal retraction, and inflammation. Since inflammation is a hallmark of most neurological conditions, we hypothesized that LPA could be involved in the physiopathology of amyotrophic lateral sclerosis (ALS). We found that LPA RNA was upregulated in post-mortem spinal cord samples of ALS patients and in the sciatic nerve and skeletal muscle of SOD1 mouse, the most widely used ALS mouse model. To assess the contribution of LPA to ALS, we generated a SOD1 mouse that was deficient in . This animal revealed that LPA signaling accelerates disease onset and neurological decline but, unexpectedly, extended the lifespan. To gain insights into the early harmful actions of LPA in ALS, we studied the effects of this receptor in the spinal cord, peripheral nerve, and skeletal muscle of ALS mice. We found that LPA gene deletion increased microglial activation but did not contribute to motoneuron death, astrogliosis, degeneration, and demyelination of motor axons. However, we observed that deficiency protected against muscle atrophy. Moreover, we also found the deletion of reduced the invasion of macrophages into the skeletal muscle of SOD1 mice, linking LPA signaling with muscle inflammation and atrophy in ALS. Overall, these results suggest for the first time that LPA contributes to ALS, and its genetic deletion results in protective actions at the early stages of the disease but shortens survival thereafter.
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http://dx.doi.org/10.3389/fncel.2021.600872DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026865PMC
March 2021

Specific Expression of Glial-Derived Neurotrophic Factor in Muscles as Gene Therapy Strategy for Amyotrophic Lateral Sclerosis.

Neurotherapeutics 2021 Mar 30. Epub 2021 Mar 30.

Institute of Neurosciences, Universitat Autònoma de Barcelona, 08193, Bellaterra, Spain.

Glial cell line-derived neurotrophic factor (GDNF) is a powerful neuroprotective growth factor. However, systemic or intrathecal administration of GDNF is associated with side effects. Here, we aimed to avoid this by restricting the transgene expression to the skeletal muscle by gene therapy. To specifically target most skeletal muscles in the mouse model of amyotrophic lateral sclerosis (ALS), SOD1 transgenic mice were intravenously injected with adeno-associated vectors coding for GDNF under the control of the desmin promoter. Treated and control SOD1 mice were evaluated by rotarod and nerve conduction tests from 8 to 20 weeks of age, and then histological and molecular analyses were performed. Muscle-specific GDNF expression delayed the progression of the disease in SOD1 female and male mice by preserving the neuromuscular function; increasing the number of innervated neuromuscular junctions, the survival of spinal motoneurons; and reducing glial reactivity in treated SOD1 mice. These beneficial actions are attributed to a paracrine protective mechanism from the muscle to the motoneurons by GDNF. Importantly, no adverse secondary effects were detected. These results highlight the potential of muscle GDNF-targeted expression for ALS therapy.
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http://dx.doi.org/10.1007/s13311-021-01025-6DOI Listing
March 2021

IL-37 exerts therapeutic effects in experimental autoimmune encephalomyelitis through the receptor complex IL-1R5/IL-1R8.

Theranostics 2021 1;11(1):1-13. Epub 2021 Jan 1.

Institut de Neurociencies and Departament de Biologia Cel·lular, Fisiologia i Immunologia, Universitat Autonoma de Barcelona, Bellaterra, Catalonia, Spain.

Interleukin 37 (IL-37), a member of IL-1 family, broadly suppresses inflammation in many pathological conditions by acting as a dual-function cytokine in that IL-37 signals via the extracellular receptor complex IL1-R5/IL-1R8, but it can also translocate to the nucleus. However, whether IL-37 exerts beneficial actions in neuroinflammatory diseases, such as multiple sclerosis, remains to be elucidated. Thus, the goals of the present study were to evaluate the therapeutic effects of IL-37 in a mouse model of multiple sclerosis, and if so, whether this is mediated via the extracellular receptor complex IL-1R5/IL-1R8. We used a murine model of MS, the experimental autoimmune encephalomyelitis (EAE). We induced EAE in three different single and double transgenic mice (hIL-37tg, IL-1R8 KO, hIL-37tg-IL-1R8 KO) and wild type littermates. We also induced EAE in C57Bl/6 mice and treated them with various forms of recombinant human IL-37 protein. Functional and histological techniques were used to assess locomotor deficits and demyelination. Luminex and flow cytometry analysis were done to assess the protein levels of pro-inflammatory cytokines and different immune cell populations, respectively. qPCRs were done to assess the expression of IL-37, IL-1R5 and IL-1R8 in the spinal cord of EAE, and in blood peripheral mononuclear cells and brain tissue samples of MS patients. We demonstrate that IL-37 reduces inflammation and protects against neurological deficits and myelin loss in EAE mice by acting via IL1-R5/IL1-R8. We also reveal that administration of recombinant human IL-37 exerts therapeutic actions in EAE mice. We finally show that IL-37 transcripts are not up-regulated in peripheral blood mononuclear cells and in brain lesions of MS patients, despite the IL-1R5/IL-1R8 receptor complex is expressed. This study presents novel data indicating that IL-37 exerts therapeutic effects in EAE by acting through the extracellular receptor complex IL-1R5/IL-1R8, and that this protective physiological mechanism is defective in MS individuals. IL-37 may therefore represent a novel therapeutic avenue for the treatment of MS with great promising potential.
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http://dx.doi.org/10.7150/thno.47435DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7681099PMC
January 2021

IL-37 Expression Is Downregulated in Lesional Psoriasis Skin.

Immunohorizons 2020 11 25;4(11):754-761. Epub 2020 Nov 25.

Department of Dermatology, Aarhus University Hospital, 8000 Aarhus, Denmark.

IL-37 broadly suppresses inflammation in various disease models. However, studies of the regulation and role of IL-37 in psoriasis are limited and contradictive. Using transcriptome analysis, PCR, protein determination, and immunofluorescence, we demonstrated marked downregulation of IL-37 in biopsies from human lesional psoriasis skin compared with paired samples of nonlesional skin. Immunofluorescence analysis showed that IL-37 was localized to stratum granulosum of the epidermis. TNF-α stimulation of normal human epidermal keratinocytes led to increased expression through a p38 MAPK-mediated mechanism, whereas IL-17A, IL-17C, IL-17F, and IL-22 acted suppressively. Intradermal injection with recombinant human IL-37 into imiquimod-induced psoriasis skin of C57BL/6J mice demonstrated a trend toward a protective effect, however NS. Altogether, these results demonstrate that IL-37 is downregulated in human lesional psoriasis skin. This may be a consequence of the loss of stratum granulosum, but key cytokines in the development of psoriasis also seem to contribute to this downregulation.
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http://dx.doi.org/10.4049/immunohorizons.2000083DOI Listing
November 2020

Extracellular and nuclear roles of IL-37 after spinal cord injury.

Brain Behav Immun 2021 01 28;91:194-201. Epub 2020 Sep 28.

Departament de Biologia Cel·lular, Fisiologia i Immunologia, Institut de Neurociències, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Universitat Autonoma de Barcelona, Bellaterra, Catalonia 08193, Spain. Electronic address:

Interleukin 37 (IL-37) is an anti-inflammatory cytokine of the interleukin 1 family. Transgenic mice expressing the human form of the IL37 gene (hIL-37Tg) display protective effects in several animal models of disease. Previous data from our group revealed that IL-37 limits inflammation after spinal cord injury (SCI) and ameliorates tissue damage and functional deficits. IL-37 can exert its anti-inflammatory effects by translocating to the nucleus or acting as an extracellular cytokine. However, whether this protection after SCI is mediated by translocating to the nucleus, activating of extracellular receptors, or both, is currently unknown. In the present study, we used different transgenic animals to answer this question. We demonstrated that the beneficial effects of IL-37 on functional and histological outcomes after SCI were lost in the lack of the extracellular receptor IL-1R8, indicating that IL-37 induces protection as an extracellular cytokine. On the other hand, transgenic mice with the nuclear function of IL-37 abolished (hIL-37D20ATg) showed significant improvement in locomotor skills and myelin sparing after SCI, indicating that nuclear pathway is not required for the protective actions of IL-37. Moreover, we also showed that the therapeutic effects of the recombinant IL-37 protein are produced only in the presence of the extracellular receptor IL-1R8, further highlighting the importance of the extracellular function of this cytokine after SCI. Finally, we revealed that the administration of recombinant IL-37 protein exerted therapeutic actions when administered in the lesion site but not systemically. This work demonstrated for the first time that translocation of IL-37 to the nucleus is not required for the beneficial actions of this cytokine after SCI and highlights the importance of the extracellular signaling of IL-37 to mediate neuroprotective actions.
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http://dx.doi.org/10.1016/j.bbi.2020.09.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7749842PMC
January 2021

CD300f immunoreceptor is associated with major depressive disorder and decreased microglial metabolic fitness.

Proc Natl Acad Sci U S A 2020 03 9;117(12):6651-6662. Epub 2020 Mar 9.

Neuroinflammation and Gene Therapy Laboratory, Institut Pasteur de Montevideo, 11400 Montevideo, Uruguay;

A role for microglia in neuropsychiatric diseases, including major depressive disorder (MDD), has been postulated. Regulation of microglial phenotype by immune receptors has become a central topic in many neurological conditions. We explored preclinical and clinical evidence for the role of the CD300f immune receptor in the fine regulation of microglial phenotype and its contribution to MDD. We found that a prevalent nonsynonymous single-nucleotide polymorphism (C/T, rs2034310) of the human CD300f receptor cytoplasmic tail inhibits the protein kinase C phosphorylation of a threonine and is associated with protection against MDD, mainly in women. Interestingly, CD300f mice displayed several characteristic MDD traits such as augmented microglial numbers, increased interleukin 6 and interleukin 1 receptor antagonist messenger RNA, alterations in synaptic strength, and noradrenaline-dependent and persistent depressive-like and anhedonic behaviors in females. This behavioral phenotype could be potentiated inducing the lipopolysaccharide depression model. RNA sequencing and biochemical studies revealed an association with impaired microglial metabolic fitness. In conclusion, we report a clear association that links the function of the CD300f immune receptor with MDD in humans, depressive-like and anhedonic behaviors in female mice, and altered microglial metabolic reprogramming.
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http://dx.doi.org/10.1073/pnas.1911816117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7104369PMC
March 2020

Combined intramuscular and intraspinal transplant of bone marrow cells improves neuromuscular function in the SOD1 mice.

Stem Cell Res Ther 2020 02 7;11(1):53. Epub 2020 Feb 7.

Institute of Neurosciences and Department of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, Barcelona, Spain.

Background: The simultaneous contribution of several etiopathogenic disturbances makes amyotrophic lateral sclerosis (ALS) a fatal and challenging disease. Here, we studied two different cell therapy protocols to protect both central and peripheral nervous system in a murine model of ALS.

Methods: Since ALS begins with a distal axonopathy, in a first assay, we performed injection of bone marrow cells into two hindlimb muscles of transgenic SOD1 mice. In a second study, we combined intramuscular and intraspinal injection of bone marrow cells. Fluorescence-activated cell sorting was used to assess the survival of the transplanted cells into the injected tissues. The mice were assessed from 8 to 16 weeks of age by means of locomotion and electrophysiological tests. After follow-up, the spinal cord was processed for analysis of motoneuron survival and glial cell reactivity.

Results: We found that, after intramuscular injection, bone marrow cells were able to engraft within the muscle. However, bone marrow cell intramuscular injection failed to promote a general therapeutic effect. In the second approach, we found that bone marrow cells had limited survival in the spinal cord, but this strategy significantly improved motor outcomes. Moreover, we also found that the dual cell therapy tended to preserve spinal motoneurons at late stages of the disease and to reduce microgliosis, although this did not prolong mice survival.

Conclusion: Overall, our findings suggest that targeting more than one affected area of the motor system at once with bone marrow cell therapy results in a valuable therapeutic intervention for ALS.
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http://dx.doi.org/10.1186/s13287-020-1573-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7006400PMC
February 2020

Gene therapy for overexpressing Neuregulin 1 type I in skeletal muscles promotes functional improvement in the SOD1 ALS mice.

Neurobiol Dis 2020 04 4;137:104793. Epub 2020 Feb 4.

Department of Cell Biology, Physiology and Immunology, Institute of Neurosciences, Universitat Autonoma de Barcelona, Bellaterra, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Bellaterra, Spain. Electronic address:

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder affecting motoneurons (MNs), with no effective treatment currently available. The molecular mechanisms that are involved in MN death are complex and not fully understood, with partial contributions of surrounding glial cells and skeletal muscle to the disease. Neuregulin 1 (NRG1) is a trophic factor highly expressed in MNs and neuromuscular junctions. Recent studies have suggested a crucial role of the isoform I (NRG1-I) in the collateral reinnervation process in skeletal muscle, and NRG1-III in the preservation of MNs in the spinal cord, opening a window for developing novel therapies for neuromuscular diseases like ALS. In this study, we overexpressed NRG1-I widely in the skeletal muscles of the SOD1 transgenic mouse. The results show that NRG1 gene therapy activated the survival pathways in muscle and spinal cord, increasing the number of surviving MNs and neuromuscular junctions and reducing the astroglial reactivity in the spinal cord of the treated SOD1 mice. Furthermore, NRG1-I overexpression preserved motor function and delayed the onset of clinical disease. In summary, our data indicates that NRG1 plays an important role on MN survival and muscle innervation in ALS, and that viral-mediated overexpression of NRG1 isoforms may be considered as a promising approach for ALS treatment.
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http://dx.doi.org/10.1016/j.nbd.2020.104793DOI Listing
April 2020

A Novel Agonist of the Type 1 Lysophosphatidic Acid Receptor (LPA), UCM-05194, Shows Efficacy in Neuropathic Pain Amelioration.

J Med Chem 2020 03 16;63(5):2372-2390. Epub 2019 Dec 16.

Departamento de Química Orgánica I, Facultad de Ciencias Químicas, Universidad Complutense de Madrid, E-28040 Madrid, Spain.

Neuropathic pain (NP) is a complex chronic pain state with a prevalence of almost 10% in the general population. Pharmacological options for NP are limited and weakly effective, so there is a need to develop more efficacious NP attenuating drugs. Activation of the type 1 lysophosphatidic acid (LPA) receptor is a crucial factor in the initiation of NP. Hence, it is conceivable that a functional antagonism strategy could lead to NP mitigation. Here we describe a new series of LPA agonists among which derivative ()- (UCM-05194) stands out as the most potent and selective LPA receptor agonist described so far ( = 118%, EC = 0.24 μM, = 19.6 nM; inactive at autotaxin and LPA receptors). This compound induces characteristic LPA-mediated cellular effects and prompts the internalization of the receptor leading to its functional inactivation in primary sensory neurons and to an efficacious attenuation of the pain perception in an model of NP.
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http://dx.doi.org/10.1021/acs.jmedchem.9b01287DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7344333PMC
March 2020

OLT1177 (Dapansutrile), a Selective NLRP3 Inflammasome Inhibitor, Ameliorates Experimental Autoimmune Encephalomyelitis Pathogenesis.

Front Immunol 2019 1;10:2578. Epub 2019 Nov 1.

Institut de Neurociencies and Departament de Biologia Cellular, Fisiologia i Immunologia, Universitat Autonoma de Barcelona, Bellaterra, Spain.

IL-1β and IL-18 are pro-inflammatory cytokines that are linked to inflammation. Activation of the NOD-like receptor protein 3 (NLRP3) inflammasome is involved in the maturation and secretion of IL-1β and IL-18 and, thus, plays a key role in the pathogenesis of many inflammatory conditions, including multiple sclerosis (MS). OLT1177™ (Dapansutrile) is a newly developed drug that is safe in humans and inhibits specifically the NLRP3 inflammasome. In the present study, we investigated whether OLT1177 exerts therapeutic effects in experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. We found that EAE mice fed an OLT1177-enriched diet prophylactically were significantly protected against functional deficits and demyelination in the spinal cord. We also demonstrated that prophylactic oral administration of OLT1177 led to marked reduction (~2- to 3-fold) in the protein levels of IL-1β and IL-18, as well as, IL-6 and TNFα, in the spinal cord of EAE mice. Moreover, prophylactic oral administration of OLT1177 significantly attenuated the infiltration of CD4 T cells and macrophages in the spinal cord. We also demonstrated that oral administration of OLT1177, starting at disease onset, resulted in significant amelioration of the clinical signs of EAE. Overall, these first data suggest that OLT1177 could have clinical benefit for the treatment of MS in humans.
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http://dx.doi.org/10.3389/fimmu.2019.02578DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6839275PMC
November 2020

Bioactive Lipids in Inflammation After Central Nervous System Injury.

Adv Exp Med Biol 2019 ;1127:181-194

Centre for Research in Neuroscience, The Research Institute of the McGill University Health Center, Montreal, Quebec, Canada.

Despite the progress made over the last decades to understand the mechanisms underlying tissue damage and neurological deficits after neurotrauma, there are currently no effective treatments in the clinic. It is well accepted that the inflammatory response in the CNS after injury exacerbates tissue loss and functional impairments. Unfortunately, the use of potent anti-inflammatory drugs, such as methylprednisolone, fails to promote therapeutic recovery and also gives rise to several undesirable side effects related to immunosuppression. The injury-induced inflammatory response is complex, and understanding the mechanisms that regulate this inflammation is therefore crucial in the quest to develop effective treatments. Bioactive lipids have emerged as potent molecules in controlling the initiation, coordination, and resolution of inflammation and in promoting tissue repair and recovery of homeostasis. These bioactive lipids are produced by cells involved in the inflammatory response, and their defective synthesis leads to persistent chronic inflammation, tissue damage, and fibrosis. The present chapter discusses recent evidence for the role of some of these bioactive lipids, in particular, eicosanoid and pro-resolving lipid mediators, in the regulation of inflammation after neurotrauma and highlights the therapeutic potential of some of these lipids in enhancing neurological outcomes after CNS injuries.
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http://dx.doi.org/10.1007/978-3-030-11488-6_12DOI Listing
August 2019

Role for nuclear interleukin-37 in the suppression of innate immunity.

Proc Natl Acad Sci U S A 2019 03 21;116(10):4456-4461. Epub 2019 Feb 21.

Department of Medicine, University of Colorado Denver, Aurora, CO 80045;

The IL-1 family member IL-37 broadly suppresses innate inflammation and acquired immunity. Similar to IL-1α and IL-33, IL-37 is a dual-function cytokine in that IL-37 translocates to the nucleus but also transmits a signal via surface membrane receptors. The role of nuclear IL-37 remains unknown on the ability of this cytokine to inhibit innate inflammation. Here, we compared suppression of innate inflammation in transgenic mice expressing native human IL-37 (IL-37Tg) with those of transgenic mice carrying the mutation of aspartic acid (D) to alanine (A) at amino acid 20 (IL-37D20ATg). The mutation D20A prevents cleavage of caspase-1, a step required for IL-37 nuclear translocation. In vitro, peritoneal macrophages from IL-37Tg mice reduced LPS-induced IL-1β, IL-6, TNFα and IFNγ by 40-50% whereas in macrophages from IL-37D20ATg mice this suppression was not observed, consistent with loss of nuclear function. Compared with macrophages from IL-37Tg mice, significantly less or no suppression of LPS-induced MAP kinase and NFκB activation was also observed in macrophages from IL-37D20ATg mice. In vivo, levels of IL-1β, IL-6, and TNFα in the lungs and liver were markedly reduced during endotoxemia in IL-37Tg mice but not observed in IL-37D20ATg mice. However, suppression of innate inflammation remains intact in the IL-37D20A mice once the cytokine is released from the cell and binds to its receptor. These studies reveal a nuclear function for suppression of innate inflammation and are consistent with the dual function of IL-37 and a role for caspase-1 in limiting inflammation.
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http://dx.doi.org/10.1073/pnas.1821111116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6410848PMC
March 2019

Lysophosphatidic acid receptor type 2 activation contributes to secondary damage after spinal cord injury in mice.

Brain Behav Immun 2019 02 11;76:258-267. Epub 2018 Dec 11.

Departament de Biologia Cel·lular, Fisiologia i Immunologia, Institut de Neurociències, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Universitat Autònoma de Barcelona, Bellaterra, Catalonia 08193, Spain. Electronic address:

Lysophosphatidic acid (LPA) is an extracellular lipid mediator involved in many physiological functions by signaling through six known G-protein-coupled receptors (LPA-LPA). In the central nervous system (CNS), LPA mediates a wide range of effects, including neural progenitor cell physiology, astrocyte and microglia activation, neuronal cell death, axonal retraction, and contributions to pain, schizophrenia and hydrocephalus. We recently reported that LPA-LPA signaling mediates functional deficits and myelin loss after spinal cord injury (SCI). Here, we provide clear evidence on the deleterious contribution of another LPA receptor, LPA, to myelin loss after SCI. We found that LPA is constitutively expressed in the spinal cord parenchyma and its transcripts were up-regulated after contusion injury, in part, by microglial cells. We also found that the demyelinating lesion triggered by intraspinal injection of LPA into the undamaged spinal cord was markedly reduced in the lack of LPA. Similarly, LPA deficient mice showed enhanced motor skills and myelin sparing after SCI. To gain insights into the detrimental actions of LPA in spinal cord we performed cell culture studies. These experiments revealed that, similar to LPA, activation of microglia LPA led to oligodendrocyte cell death. Moreover, we also found that the cytotoxic effects underlaying microglial LPA-LPA axis were mediated by the release of purines by microglia and the activation of PX receptor on oligodendrocytes. Overall, this study provides new mechanistic insights into how LPA contributes to SCI physiopathology, and suggest that targeting LPA could be a novel therapeutic approach for the treatment of acute SCI.
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http://dx.doi.org/10.1016/j.bbi.2018.12.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6348147PMC
February 2019

Neuroinflammation Quantification for Spinal Cord Injury.

Curr Protoc Immunol 2018 11 25;123(1):e57. Epub 2018 Sep 25.

Institut de Neurociencies and Departament de Biologia Cellular, Fisiologia i Immunologia, Universitat Autonoma de Barcelona, and CIBERNED, Bellaterra, Spain.

Spinal cord injury (SCI) leads to irreversible devastating neurological disabilities. Accumulated evidence in the literature indicates that the inflammatory response that occurs in the spinal cord following injury contributes importantly to spread tissue damage to healthy regions adjacent to the lesion site, and consequently, to increase neurological deficits. Therefore, targeting inflammation could lead to the development of new therapies to prevent tissue damage and neurological impairments after SCI. Inflammation is regulated, in part, by the expression of pro-inflammatory and anti-inflammatory cytokines synthesized, mainly, by glial cells. Hence, methodologies that could ease the quantification of multiple cytokines and immune cells from spinal cord tissue samples are needed to assess the potential of new anti-inflammatory therapies. In the present unit, we describe how to induce contusion injuries in the mouse spinal cord, as well as, two useful methodologies to assess neuroinflammation in lesioned spinal cord tissue samples. © 2018 by John Wiley & Sons, Inc.
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http://dx.doi.org/10.1002/cpim.57DOI Listing
November 2018

Myeloid cell responses after spinal cord injury.

J Neuroimmunol 2018 08 6;321:97-108. Epub 2018 Jun 6.

Departament de Biologia Cellular, Fisiologia i Immunologia, Institut de Neurociències, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Universitat Autònoma de Barcelona, 08193 Bellaterra, Catalonia, Spain.

The past decade has revealed much about the complexity of the local inflammatory response after spinal cord injury (SCI). A major challenge is to distinguish between microglia and monocyte-derived macrophages (MDMs) to determine their phenotype and function. Transcriptome studies have revealed microglia-selective genes but are still limited in scope because many markers are downregulated after injury. Additionally, new genetic reporter mice are available to study microglia and MDMs. There is more evidence now for the plasticity and heterogeneity of microglia and MDMs. We also discuss the role of neutrophils that are the first peripheral cells to enter the injured CNS.
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http://dx.doi.org/10.1016/j.jneuroim.2018.06.003DOI Listing
August 2018

CD200 modulates spinal cord injury neuroinflammation and outcome through CD200R1.

Brain Behav Immun 2018 10 2;73:416-426. Epub 2018 Jun 2.

Neuroinflammation and Gene Therapy Laboratory, Institut Pasteur de Montevideo, Mataojo 2020, 11400 Montevideo, Uruguay; Department of Histology and Embryology, Faculty of Medicine, UDELAR, Montevideo, Uruguay.

The interaction between CD200 and its receptor CD200R1 is among the central regulators of microglia and macrophage phenotype. However, it remains to be established whether, in the context of a traumatic CNS injury, CD200R1 act as a negative regulator of these particular innate immune cells, and if the exogenous delivery of CD200 may ameliorate neurological deficits. In the present study, we first evaluated whether preventing the local interaction between the pair CD200-CD200R1, by using a selective blocking antibody against CD200R1, has a role on functional and inflammatory outcome after contusion-induced spinal cord injury (SCI) in mice. The injection of the αCD200R1, but not control IgG1, into the lesioned spinal cord immediately after the SCI worsened locomotor performance and exacerbated neuronal loss and demyelination. At the neuroimmunological level, we observed that microglial cells and macrophages showed increased levels of iNOS and Ly6C upon CD200R1 blockade, indicating that the disruption of CD200R1 drove these cells towards a more pro-inflammatory phenotype. Moreover, although CD200R1 blockade had no effect in the initial infiltration of neutrophils into the lesioned spinal cord, it significantly impaired their clearance, which is a key sign of excessive inflammation. Interestingly, intraparenchymal injection of recombinant CD200-His immediately after the injury induced neuroprotection and robust and long-lasting locomotor recovery. In conclusion, this study reveals that interaction of CD200-CD200R1 plays a crucial role in limiting inflammation and lesion progression after SCI, and that boosting the stimulation of this pathway may constitute a new therapeutic approach.
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http://dx.doi.org/10.1016/j.bbi.2018.06.002DOI Listing
October 2018

Maresin 1 Promotes Inflammatory Resolution, Neuroprotection, and Functional Neurological Recovery After Spinal Cord Injury.

J Neurosci 2017 Nov 6;37(48):11731-11743. Epub 2017 Nov 6.

Departament de Biologia Cel·lular, Fisiologia i Immunologia, Institut de Neurociencies, Centro de Investigacio'n Biome'dica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Universitat Autonoma de Barcelona, 08193 Bellaterra, Catalonia, Spain,

Resolution of inflammation is defective after spinal cord injury (SCI), which impairs tissue integrity and remodeling and leads to functional deficits. Effective pharmacological treatments for SCI are not currently available. Maresin 1 (MaR1) is a highly conserved specialized proresolving mediator (SPM) hosting potent anti-inflammatory and proresolving properties with potent tissue regenerative actions. Here, we provide evidence that the inappropriate biosynthesis of SPM in the lesioned spinal cord hampers the resolution of inflammation and leads to deleterious consequences on neurological outcome in adult female mice. We report that, after spinal cord contusion injury in adult female mice, the biosynthesis of SPM is not induced in the lesion site up to 2 weeks after injury. Exogenous administration of MaR1, a highly conserved SPM, propagated inflammatory resolution after SCI, as revealed by accelerated clearance of neutrophils and a reduction in macrophage accumulation at the lesion site. In the search of mechanisms underlying the proresolving actions of MaR1 in SCI, we found that this SPM facilitated several hallmarks of resolution of inflammation, including reduction of proinflammatory cytokines (CXCL1, CXCL2, CCL3, CCL4, IL6, and CSF3), silencing of major inflammatory intracellular signaling cascades (STAT1, STAT3, STAT5, p38, and ERK1/2), redirection of macrophage activation toward a prorepair phenotype, and increase of the phagocytic engulfment of neutrophils by macrophages. Interestingly, MaR1 administration improved locomotor recovery significantly and mitigated secondary injury progression in a clinical relevant model of SCI. These findings suggest that proresolution, immunoresolvent therapies constitute a novel approach to improving neurological recovery after acute SCI. Inflammation is a protective response to injury or infection. To result in tissue homeostasis, inflammation has to resolve over time. Incomplete or delayed resolution leads to detrimental effects, including propagated tissue damage and impaired wound healing, as occurs after spinal cord injury (SCI). We report that inflammation after SCI is dysregulated in part due to inappropriate synthesis of proresolving lipid mediators. We demonstrate that the administration of the resolution agonist referred to as maresin 1 (MaR1) after SCI actively propagates resolution processes at the lesion site and improves neurological outcome. MaR1 is identified as an interventional candidate to attenuate dysregulated lesional inflammation and to restore functional recovery after SCI.
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http://dx.doi.org/10.1523/JNEUROSCI.1395-17.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5707767PMC
November 2017

IL-4 drives microglia and macrophages toward a phenotype conducive for tissue repair and functional recovery after spinal cord injury.

Glia 2016 12 29;64(12):2079-2092. Epub 2016 Jul 29.

Departament De Biologia Cel·lular, Fisiologia I Immunologia, Institut De Neurociències, Centro De Investigación Biomédica En Red Sobre Enfermedades Neurodegenerativas (CIBERNED), Universitat Autònoma De Barcelona, Bellaterra, Catalonia, 08193, Spain.

Macrophages and microglia play a key role in the maintenance of nervous system homeostasis. However, upon different challenges, they can adopt several phenotypes, which may lead to divergent effects on tissue repair. After spinal cord injury (SCI), microglia and macrophages show predominantly pro-inflammatory activation and contribute to tissue damage. However, the factors that hamper their conversion to an anti-inflammatory state after SCI, or to other protective phenotypes, are poorly understood. Here, we show that IL-4 protein levels are undetectable in the spinal cord after contusion injury, which likely favors microglia and macrophages to remain in a pro-inflammatory state. We also demonstrate that a single delayed intraspinal injection of IL-4, 48 hours after SCI, induces increased expression of M2 marker in microglia and macrophages. We also show that delayed injection of IL-4 leads to the appearance of resolution-phase macrophages, and that IL-4 enhances resolution of inflammation after SCI. Interestingly, we provide clear evidence that delayed administration of IL-4 markedly improves functional outcomes and reduces tissue damage after contusion injury. It is possible that these improvements are mediated by the presence of macrophages with M2 markers and resolution-phase macrophages. These data suggest that therapies aimed at increasing IL-4 levels could be valuable for the treatment of acute SCI, for which there are currently no effective treatments. GLIA 2016;64:2079-2092.
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http://dx.doi.org/10.1002/glia.23041DOI Listing
December 2016

CSF1R blockade slows the progression of amyotrophic lateral sclerosis by reducing microgliosis and invasion of macrophages into peripheral nerves.

Sci Rep 2016 05 13;6:25663. Epub 2016 May 13.

Institut de Neurociencies, Department Biologia Cellular, Fisiologia i Immunologia, Universitat Autònoma de Barcelona, and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Bellaterra, Spain.

Inflammation is a common neuropathological feature in several neurological disorders, including amyotrophic lateral sclerosis (ALS). We have studied the contribution of CSF1R signalling to inflammation in ALS, as a pathway previously reported to control the expansion and activation of microglial cells. We found that microglial cell proliferation in the spinal cord of SOD1(G93A) transgenic mice correlates with the expression of CSF1R and its ligand CSF1. Administration of GW2580, a selective CSF1R inhibitor, reduced microglial cell proliferation in SOD1(G93A) mice, indicating the importance of CSF1-CSF1R signalling in microgliosis in ALS. Moreover, GW2580 treatment slowed disease progression, attenuated motoneuron cell death and extended survival of SOD1(G93A) mice. Electrophysiological assessment revealed that GW2580 treatment protected skeletal muscle from denervation prior to its effects on microglial cells. We found that macrophages invaded the peripheral nerve of ALS mice before CSF1R-induced microgliosis occurred. Interestingly, treatment with GW2580 attenuated the influx of macrophages into the nerve, which was partly caused by the monocytopenia induced by CSF1R inhibition. Overall, our findings provide evidence that CSF1R signalling regulates inflammation in the central and peripheral nervous system in ALS, supporting therapeutic targeting of CSF1R in this disease.
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http://dx.doi.org/10.1038/srep25663DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4865981PMC
May 2016

Beneficial effects of IL-37 after spinal cord injury in mice.

Proc Natl Acad Sci U S A 2016 Feb 19;113(5):1411-6. Epub 2016 Jan 19.

Departament de Biologia Cellular, Fisiologia i Immunologia, Institut de Neurociències, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain;

IL-37, a member of the IL-1 family, broadly reduces innate inflammation as well as acquired immunity. Whether the antiinflammatory properties of IL-37 extend to the central nervous system remains unknown, however. In the present study, we subjected mice transgenic for human IL-37 (hIL-37tg) and wild-type (WT) mice to spinal cord contusion injury and then treated them with recombinant human IL-37 (rIL-37). In the hIL-37tg mice, the expression of IL-37 was barely detectable in the uninjured cords, but was strongly induced at 24 h and 72 h after the spinal cord injury (SCI). Compared with WT mice, hIL-37tg mice exhibited increased myelin and neuronal sparing and protection against locomotor deficits, including 2.5-fold greater speed in a forced treadmill challenge. Reduced levels of cytokines (e.g., an 80% reduction in IL-6) were observed in the injured cords of hIL-37tg mice, along with lower numbers of blood-borne neutrophils, macrophages, and activated microglia. We treated WT mice with a single intraspinal injection of either full-length or processed rIL-37 after the injury and found that the IL-37-treated mice had significantly enhanced locomotor skills in an open field using the Basso Mouse Scale, as well as supported faster speed on a mechanical treadmill. Treatment with both forms of rIL-37 led to similar beneficial effects on locomotor recovery after SCI. This study presents novel data indicating that IL-37 suppresses inflammation in a clinically relevant model of SCI, and suggests that rIL-37 may have therapeutic potential for the treatment of acute SCI.
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http://dx.doi.org/10.1073/pnas.1523212113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4747716PMC
February 2016

CD300f immunoreceptor contributes to peripheral nerve regeneration by the modulation of macrophage inflammatory phenotype.

J Neuroinflammation 2015 Aug 12;12:145. Epub 2015 Aug 12.

Neuroinflammation and Gene Therapy Laboratory, Institut Pasteur Montevideo, Mataojo 2020, CP 11400, Montevideo, Uruguay.

Background: It has recently become evident that activating/inhibitory cell surface immune receptors play a critical role in regulating immune and inflammatory processes in the central nervous system (CNS). The immunoreceptor CD300f expressed on monocytes, neutrophils, and mast cells modulates inflammation, phagocytosis, and outcome in models of autoimmune demyelination, allergy, and systemic lupus erythematosus. On the other hand, a finely regulated inflammatory response is essential to induce regeneration after injury to peripheral nerves since hematogenous macrophages, together with resident macrophages and de-differentiated Schwann cells, phagocyte distal axonal and myelin debris in a well-orchestrated inflammatory response. The possible roles and expression of CD300f and its ligands have not been reported under these conditions.

Methods: By using quantitative PCR (QPCR) and CD300f-IgG2a fusion protein, we show the expression of CD300f and its ligands in the normal and crush injured sciatic nerve. The putative role of CD300f in peripheral nerve regeneration was analyzed by blocking receptor-ligand interaction with the same CD300f-IgG2a soluble receptor fusion protein in sciatic nerves of Thy1-YFP-H mice injected at the time of injury. Macrophage M1/M2 polarization phenotype was also analyzed by CD206 and iNOS expression.

Results: We found an upregulation of CD300f mRNA and protein expression after injury. Moreover, the ligands are present in restricted membrane patches of Schwann cells, which remain stable after the lesion. The lesioned sciatic nerves of Thy1-YFP-H mice injected with a single dose of CD300f-IgG2a show long lasting effects on nerve regeneration characterized by a lower number of YFP-positive fibres growing into the tibial nerve after 10 days post lesion (dpl) and a delayed functional recovery when compared to PBS- or IgG2a-administered control groups. Animals treated with CD300f-IgG2a show at 10 dpl higher numbers of macrophages and CD206-positive cells and lower levels of iNOS expression than both control groups. At later time points (28 dpl), increased numbers of macrophages and iNOS expression occur.

Conclusions: Taken together, these results show that the pair CD300f ligand is implicated in Wallerian degeneration and nerve regeneration by modulating both the influx and phenotype of macrophages.
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http://dx.doi.org/10.1186/s12974-015-0364-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4531482PMC
August 2015

Activation of Lysophosphatidic Acid Receptor Type 1 Contributes to Pathophysiology of Spinal Cord Injury.

J Neurosci 2015 Jul;35(28):10224-35

Department of Cellular Biology, Physiology, and Immunology, Institute of Neurosciences, Center for Biomedical Research in Neurodegenerative Diseases Network (CIBERNED), Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain,

Unlabelled: Lysophosphatidic acid (LPA) is an extracellular lipid mediator involved in many physiological functions that signals through six known G-protein-coupled receptors (LPA1-LPA6). A wide range of LPA effects have been identified in the CNS, including neural progenitor cell physiology, astrocyte and microglia activation, neuronal cell death, axonal retraction, and development of neuropathic pain. However, little is known about the involvement of LPA in CNS pathologies. Herein, we demonstrate for the first time that LPA signaling via LPA1 contributes to secondary damage after spinal cord injury. LPA levels increase in the contused spinal cord parenchyma during the first 14 d. To model this potential contribution of LPA in the spinal cord, we injected LPA into the normal spinal cord, revealing that LPA induces microglia/macrophage activation and demyelination. Use of a selective LPA1 antagonist or mice lacking LPA1 linked receptor-mediated signaling to demyelination, which was in part mediated by microglia. Finally, we demonstrate that selective blockade of LPA1 after spinal cord injury results in reduced demyelination and improvement in locomotor recovery. Overall, these results support LPA-LPA1 signaling as a novel pathway that contributes to secondary damage after spinal cord contusion in mice and suggest that LPA1 antagonism might be useful for the treatment of acute spinal cord injury.

Significance Statement: This study reveals that LPA signaling via LPA receptor type 1 activation causes demyelination and functional deficits after spinal cord injury.
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http://dx.doi.org/10.1523/JNEUROSCI.4703-14.2015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4502263PMC
July 2015

Lysophosphatidic acid receptor type 1 (LPA1) plays a functional role in osteoclast differentiation and bone resorption activity.

J Biol Chem 2014 Mar 15;289(10):6551-6564. Epub 2014 Jan 15.

INSERM, UMR1033, UCB Lyon 1, Faculté de Médecine Lyon Est, 69732 Lyon, France. Electronic address:

Lysophosphatidic acid (LPA) is a natural bioactive lipid that acts through six different G protein-coupled receptors (LPA1-6) with pleiotropic activities on multiple cell types. We have previously demonstrated that LPA is necessary for successful in vitro osteoclastogenesis of bone marrow cells. Bone cells controlling bone remodeling (i.e. osteoblasts, osteoclasts, and osteocytes) express LPA1, but delineating the role of this receptor in bone remodeling is still pending. Despite Lpar1(-/-) mice displaying a low bone mass phenotype, we demonstrated that bone marrow cell-induced osteoclastogenesis was reduced in Lpar1(-/-) mice but not in Lpar2(-/-) and Lpar3(-/-) animals. Expression of LPA1 was up-regulated during osteoclastogenesis, and LPA1 antagonists (Ki16425, Debio0719, and VPC12249) inhibited osteoclast differentiation. Blocking LPA1 activity with Ki16425 inhibited expression of nuclear factor of activated T-cell cytoplasmic 1 (NFATc1) and dendritic cell-specific transmembrane protein and interfered with the fusion but not the proliferation of osteoclast precursors. Similar to wild type osteoclasts treated with Ki16425, mature Lpar1(-/-) osteoclasts had reduced podosome belt and sealing zone resulting in reduced mineralized matrix resorption. Additionally, LPA1 expression markedly increased in the bone of ovariectomized mice, which was blocked by bisphosphonate treatment. Conversely, systemic treatment with Debio0719 prevented ovariectomy-induced cancellous bone loss. Moreover, intravital multiphoton microscopy revealed that Debio0719 reduced the retention of CX3CR1-EGFP(+) osteoclast precursors in bone by increasing their mobility in the bone marrow cavity. Overall, our results demonstrate that LPA1 is essential for in vitro and in vivo osteoclast activities. Therefore, LPA1 emerges as a new target for the treatment of diseases associated with excess bone loss.
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http://dx.doi.org/10.1074/jbc.M113.533232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3945319PMC
March 2014

Harmful and beneficial effects of inflammation after spinal cord injury: potential therapeutic implications.

Handb Clin Neurol 2012 ;109:485-502

McGill University Health Centre, Montreal, Canada.

Spinal cord injury (SCI) results in immediate damage followed by a secondary phase of tissue damage that occurs over a period of several weeks. The mechanisms underlying this secondary damage are multiple and not fully understood. A number of studies suggest that the local inflammatory response in the spinal cord that occurs after SCI contributes importantly to secondary damage. This response is mediated by cells normally found in the central nervous system (CNS) as well as infiltrating leukocytes. While the inflammatory response mediated by these cells is required for efficient clearance of tissue debris, and promotes wound healing and tissue repair, they also release various factors that can be detrimental to neurons, glia, axons, and myelin. In this chapter we provide an overview of the inflammatory response at the cell and molecular level after SCI, and review the current state of knowledge about its contribution to tissue damage and repair. Additionally, we discuss how some of this work is leading to the development and testing of drugs that modulate inflammation to treat acute SCI in humans.
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http://dx.doi.org/10.1016/B978-0-444-52137-8.00030-9DOI Listing
August 2013

Beneficial effects of αB-crystallin in spinal cord contusion injury.

J Neurosci 2012 Oct;32(42):14478-88

Departament de Biologia Cel.lular, Fisiologia i Immunologia, Institut de Neurociències, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Universitat Autònoma de Barcelona, 08193 Bellaterra, Catalonia, Spain.

αB-crystallin is a member of the heat shock protein family that exerts cell protection under several stress-related conditions. Recent studies have revealed that αB-crystallin plays a beneficial role in a mouse model of multiple sclerosis, brain ischemia, and Alexander disease. Whether αB-crystallin plays a role in modulating the secondary damage after CNS trauma is not known. We report here that αB-crystallin mediates protective effects after spinal cord injury. The levels of αB-crystallin are reduced in spinal cord tissue following contusion lesion. In addition, administration of recombinant human αB-crystallin for the first week after contusion injury leads to sustained improvement in locomotor skills and amelioration of secondary tissue damage. We also provide evidence that recombinant human αB-crystallin modulates the inflammatory response in the injured spinal cord, leading to increased infiltration of granulocytes and reduced recruitment of inflammatory macrophages. Furthermore, the delivery of recombinant human αB-crystallin promotes greater locomotor recovery even when the treatment is initiated 6 h after spinal cord injury. Our findings suggest that administration of recombinant human αB-crystallin may be a good therapeutic approach for treating acute spinal cord injury, for which there is currently no effective treatment.
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http://dx.doi.org/10.1523/JNEUROSCI.0923-12.2012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6621445PMC
October 2012

Role of phospholipase A2s and lipid mediators in secondary damage after spinal cord injury.

Cell Tissue Res 2012 Jul 13;349(1):249-67. Epub 2012 May 13.

Center for Research in Neuroscience, The Research Institute of the McGill University Health Center, Livingston Hall, Room L7-210, 1650 Cedar Ave., Montreal, Quebec, Canada, H3G 1A4,

Inflammation is considered to be an important contributor to secondary damage after spinal cord injury (SCI). This secondary damage leads to further exacerbation of tissue loss and functional impairments. The immune responses that are triggered by injury are complex and are mediated by a variety of factors that have both detrimental and beneficial effects. In this review, we focus on the diverse effects of the phospholipase A(2) (PLA(2)) superfamily and the downstream pathways that generate a large number of bioactive lipid mediators, some of which have pro-inflammatory and demyelinating effects, whereas others have anti-inflammatory and pro-resolution properties. For each of these lipid mediators, we provide an overview followed by a discussion of their expression and role in SCI. Where appropriate, we have compared the latter with their role in other neurological conditions. The PLA(2) pathway provides a number of targets for therapeutic intervention for the treatment of SCI and other neurological conditions.
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http://dx.doi.org/10.1007/s00441-012-1430-8DOI Listing
July 2012

Role of Ninjurin-1 in the migration of myeloid cells to central nervous system inflammatory lesions.

Ann Neurol 2011 Nov;70(5):751-63

Neuroimmunology Research Unit, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Faculté de Médecine, Université de Montréal, Montreal, Quebec, Canada.

Objective: Blood-derived myeloid antigen-presenting cells (APCs) account for a significant proportion of the leukocytes found within lesions of multiple sclerosis (MS) and experimental allergic encephalomyelitis (EAE). These APCs along with activated microglia are thought to be pivotal in the initiation of the central nervous system (CNS)-targeted immune response in MS and EAE. However, the exact molecules that direct the migration of myeloid cells from the periphery across the blood-brain barrier (BBB) remain largely unknown.

Methods: We identified Ninjurin-1 in a proteomic screen of human BBB endothelial cells (ECs). We assessed the expression of Ninjurin-1 by BBB-ECs and immune cells, and we determined the role of Ninjurin-1 in immune cell migration to the CNS in vivo in EAE mice.

Results: Ninjurin-1 was found to be weakly expressed in the healthy human and mouse CNS but upregulated on BBB-ECs and on infiltrating APCs during the course of EAE and in active MS lesions. In human peripheral blood, Ninjurin-1 was predominantly expressed by monocytes, whereas it was barely detectable on T and B lymphocytes. Moreover, Ninjurin-1 neutralization specifically abrogated the adhesion and migration of human monocytes across BBB-ECs, without affecting lymphocyte recruitment. Finally, Ninjurin-1 blockade reduced clinical disease activity and histopathological indices of EAE and decreased infiltration of macrophages, dendritic cells, and APCs into the CNS.

Interpretation: Our study uncovers an important cell-specific role for Ninjurin-1 in the transmigration of inflammatory APCs across the BBB and further emphasizes the importance of myeloid cell recruitment during the development of neuroinflammatory lesions.
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http://dx.doi.org/10.1002/ana.22519DOI Listing
November 2011

Lipocalin 2 plays an immunomodulatory role and has detrimental effects after spinal cord injury.

J Neurosci 2011 Sep;31(38):13412-9

Center for Research in Neuroscience, The Research Institute of the McGill University Health Center, Montreal, Quebec H3G1A4, Canada.

Lipocalin 2 (Lcn2) plays an important role in defense against bacterial infection by interfering with bacterial iron acquisition. Although Lcn2 is expressed in a number of aseptic inflammatory conditions, its role in these conditions remains unclear. We examined the expression and role of Lcn2 after spinal cord injury (SCI) in adult mice by using a contusion injury model. Lcn2 expression at the protein level is rapidly increased 12-fold at 1 d after SCI and decreases gradually thereafter, being three times as high as control levels at 21 d after injury. Lcn2 expression is strongly induced after contusion injury in astrocytes, neurons, and neutrophils. The Lcn2 receptor (Lcn2R), which has been shown to influence cell survival, is also expressed after SCI in the same cell types. Lcn2-deficient (Lcn2⁻/⁻) mice showed significantly better locomotor recovery after spinal cord contusion injury than wild-type (Lcn2⁺/⁺) mice. Histological assessments indicate improved neuronal and tissue survival and greater sparing of myelin in Lcn2⁻/⁻ mice after contusion injury. Flow cytometry showed a decrease in neutrophil influx and a small increase in the monocyte population in Lcn2⁻/⁻ injured spinal cords. This change was accompanied by a reduction in the expression of several pro-inflammatory chemokines and cytokines as well as inducible nitric oxide synthase early after SCI in Lcn2⁻/⁻ mice compared with wild-type animals. Our results, therefore, suggest a role for Lcn2 in regulating inflammation in the injured spinal cord and that lack of Lcn2 reduces secondary damage and improves locomotor recovery after spinal cord contusion injury.
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http://dx.doi.org/10.1523/JNEUROSCI.0116-11.2011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6623298PMC
September 2011