Publications by authors named "Tanja Kuhlmann"

104 Publications

Dietary conjugated linoleic acid links reduced intestinal inflammation to amelioration of CNS autoimmunity.

Brain 2021 May;144(4):1152-1166

Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Münster, Germany.

A close interaction between gut immune responses and distant organ-specific autoimmunity including the CNS in multiple sclerosis has been established in recent years. This so-called gut-CNS axis can be shaped by dietary factors, either directly or via indirect modulation of the gut microbiome and its metabolites. Here, we report that dietary supplementation with conjugated linoleic acid, a mixture of linoleic acid isomers, ameliorates CNS autoimmunity in a spontaneous mouse model of multiple sclerosis, accompanied by an attenuation of intestinal barrier dysfunction and inflammation as well as an increase in intestinal myeloid-derived suppressor-like cells. Protective effects of dietary supplementation with conjugated linoleic acid were not abrogated upon microbiota eradication, indicating that the microbiome is dispensable for these conjugated linoleic acid-mediated effects. Instead, we observed a range of direct anti-inflammatory effects of conjugated linoleic acid on murine myeloid cells including an enhanced IL10 production and the capacity to suppress T-cell proliferation. Finally, in a human pilot study in patients with multiple sclerosis (n = 15, under first-line disease-modifying treatment), dietary conjugated linoleic acid-supplementation for 6 months significantly enhanced the anti-inflammatory profiles as well as functional signatures of circulating myeloid cells. Together, our results identify conjugated linoleic acid as a potent modulator of the gut-CNS axis by targeting myeloid cells in the intestine, which in turn control encephalitogenic T-cell responses.
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http://dx.doi.org/10.1093/brain/awab040DOI Listing
May 2021

Donor cell memory confers a metastable state of directly converted cells.

Cell Stem Cell 2021 Apr 7. Epub 2021 Apr 7.

Department of Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Münster 48149, Germany; Faculty of Medicine, University of Münster, Münster 48149, Germany. Electronic address:

Generation of induced oligodendrocyte progenitor cells (iOPCs) from somatic fibroblasts is a strategy for cell-based therapy of myelin diseases. However, iOPC generation is inefficient, and the resulting iOPCs exhibit limited expansion and differentiation competence. Here we overcome these limitations by transducing an optimized transcription factor combination into a permissive donor phenotype, the pericyte. Pericyte-derived iOPCs (PC-iOPCs) are stably expandable and functionally myelinogenic with high differentiation competence. Unexpectedly, however, we found that PC-iOPCs are metastable so that they can produce myelination-competent oligodendrocytes or revert to their original identity in a context-dependent fashion. Phenotypic reversion of PC-iOPCs is tightly linked to memory of their original transcriptome and epigenome. Phenotypic reversion can be disconnected from this donor cell memory effect, and in vivo myelination can eventually be achieved by transplantation of O4 pre-oligodendrocytes. Our data show that donor cell source and memory can contribute to the fate and stability of directly converted cells.
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http://dx.doi.org/10.1016/j.stem.2021.02.023DOI Listing
April 2021

One-step Reprogramming of Human Fibroblasts into Oligodendrocyte-like Cells by SOX10, OLIG2, and NKX6.2.

Stem Cell Reports 2021 Apr 25;16(4):771-783. Epub 2021 Mar 25.

Institute of Neuropathology, University Hospital Münster, Pottkamp 2, 48149 Münster, Germany. Electronic address:

Limited access to human oligodendrocytes impairs better understanding of oligodendrocyte pathology in myelin diseases. Here, we describe a method to robustly convert human fibroblasts directly into oligodendrocyte-like cells (dc-hiOLs), which allows evaluation of remyelination-promoting compounds and disease modeling. Ectopic expression of SOX10, OLIG2, and NKX6.2 in human fibroblasts results in rapid generation of O4 cells, which further differentiate into MBP mature oligodendrocyte-like cells within 16 days. dc-hiOLs undergo chromatin remodeling to express oligodendrocyte markers, ensheath axons, and nanofibers in vitro, respond to promyelination compound treatment, and recapitulate in vitro oligodendroglial pathologies associated with Pelizaeus-Merzbacher leukodystrophy related to PLP1 mutations. Furthermore, DNA methylome analysis provides evidence that the CpG methylation pattern significantly differs between dc-hiOLs derived from fibroblasts of young and old donors, indicating the maintenance of the source cells' "age." In summary, dc-hiOLs represent a reproducible technology that could contribute to personalized medicine in the field of myelin diseases.
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http://dx.doi.org/10.1016/j.stemcr.2021.03.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8072064PMC
April 2021

Absence of B Cells in Brainstem and White Matter Lesions Associates With Less Severe Disease and Absence of Oligoclonal Bands in MS.

Neurol Neuroimmunol Neuroinflamm 2021 03 27;8(2). Epub 2021 Jan 27.

From the Department of Neuroimmunology (N.L.F., M.C.J.V. J.H., I.H., J.S.), Netherlands Institute for Neuroscience, Amsterdam, The Netherlands; Department of Neurology and MS Center, Amsterdam, Amsterdam Neuroscience, Amsterdam University Medical Centers, Vrije Universiteit (B.A.J.), The Netherlands; Institute for Neuropathology (K.H., T.K.), University Hospital Münster, Münster, Germany; Department of Experimental Immunology (J.H.), Amsterdam Infection & Immunity Institute, Amsterdam University Medical Centers, University of Amsterdam, The Netherlands; Swammerdam Institute for Life Sciences, University of Amsterdam (I.H.), The Netherlands; and MS Center ErasMS (J.S.), Departments of Neurology and Immunology, Erasmus Medical Center, Rotterdam, The Netherlands.

Objective: To determine whether B-cell presence in brainstem and white matter (WM) lesions is associated with poorer pathological and clinical characteristics in advanced MS autopsy cases.

Methods: Autopsy tissue of 140 MS and 24 control cases and biopsy tissue of 24 patients with MS were examined for CD20 B cells and CD138 plasma cells. The presence of these cells was compared with pathological and clinical characteristics. In corresponding CSF and plasma, immunoglobulin (Ig) G ratio and oligoclonal band (OCB) patterns were determined. In a clinical cohort of 73 patients, the presence of OCBs was determined during follow-up and compared to status at diagnosis.

Results: In 34% of active and 71% of mixed active/inactive lesions, B cells were absent, which correlated with less pronounced meningeal B-cell infiltration ( < 0.0001). The absence of B cells and plasma cells in brainstem and WM lesions was associated with a longer disease duration ( = 0.001), less frequent secondary progressive MS compared with relapsing and primary progressive MS ( < 0.0001 and = 0.046, respectively), a lower proportion of mixed active/inactive lesions ( = 0.01), and less often perivascular T-cell clustering ( < 0.0001). Moreover, a lower CSF IgG ratio ( = 0.006) and more frequent absence of OCBs ( < 0.0001) were noted. In a clinical cohort, numbers of patients without OCBs in CSF were increased at follow-up (27.4%).

Conclusions: The absence of B cells is associated with a favorable clinical and pathological profile. This finding may reflect extremes of a continuum of genetic or environmental constitution, but also a regression of WM humoral immunopathology in the natural course of advanced MS.
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http://dx.doi.org/10.1212/NXI.0000000000000955DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862088PMC
March 2021

Neuropathology associated with SARS-CoV-2 infection.

Lancet 2021 01;397(10271):276-277

Department of Pathology and Immunology, Division of Clinical Pathology, Geneva University Hospitals, Geneva 1211, Switzerland. Electronic address:

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http://dx.doi.org/10.1016/S0140-6736(21)00095-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7825940PMC
January 2021

Beneficial contribution of induced pluripotent stem cell-progeny to Connexin 47 dynamics during demyelination-remyelination.

Glia 2021 May 10;69(5):1094-1109. Epub 2020 Dec 10.

INSERM, U1127, Paris, France.

Oligodendrocytes are extensively coupled to astrocytes, a phenomenon ensuring glial homeostasis and maintenance of central nervous system myelin. Molecular disruption of this communication occurs in demyelinating diseases such as multiple sclerosis. Less is known about the vulnerability and reconstruction of the panglial network during adult demyelination-remyelination. Here, we took advantage of lysolcithin-induced demyelination to investigate the expression dynamics of the oligodendrocyte specific connexin 47 (Cx47) and to some extent that of astrocyte Cx43, and whether this dynamic could be modulated by grafted induced pluripotent stem cell (iPSC)-neural progeny. Our data show that disruption of Cx43-Cx47 mediated hetero-cellular gap-junction intercellular communication following demyelination is larger in size than demyelination. Loss of Cx47 expression is timely rescued during remyelination and accelerated by the grafted neural precursors. Moreover, mouse and human iPSC-derived oligodendrocytes express Cx47, which co-labels with astrocyte Cx43, indicating their integration into the panglial network. These data suggest that in rodents, full lesion repair following transplantation occurs by panglial reconstruction in addition to remyelination. Targeting panglial elements by cell therapy or pharmacological compounds may help accelerating or stabilizing re/myelination in myelin disorders.
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http://dx.doi.org/10.1002/glia.23950DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7984339PMC
May 2021

Multiple sclerosis iPS-derived oligodendroglia conserve their properties to functionally interact with axons and glia in vivo.

Sci Adv 2020 12 4;6(49). Epub 2020 Dec 4.

INSERM, U1127, F-75013 Paris, France.

Remyelination failure in multiple sclerosis (MS) is associated with a migration/differentiation block of oligodendroglia. The reason for this block is highly debated. It could result from disease-related extrinsic or intrinsic regulators in oligodendroglial biology. To avoid confounding immune-mediated extrinsic effect, we used an immune-deficient mouse model to compare induced pluripotent stem cell-derived oligodendroglia from MS and healthy donors following engraftment in the developing CNS. We show that the MS-progeny behaves and differentiates into oligodendrocytes to the same extent as controls. They generate equal amounts of myelin, with bona fide nodes of Ranvier, and promote equal restoration of their host slow conduction. MS-progeny expressed oligodendrocyte- and astrocyte-specific connexins and established functional connections with donor and host glia. Thus, MS oligodendroglia, regardless of major immune manipulators, are intrinsically capable of myelination and making functional axo-glia/glia-glia connections, reinforcing the view that the MS oligodendrocyte differentiation block is not from major intrinsic oligodendroglial deficits.
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http://dx.doi.org/10.1126/sciadv.abc6983DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821889PMC
December 2020

Oligodendrocyte myelin glycoprotein as a novel target for pathogenic autoimmunity in the CNS.

Acta Neuropathol Commun 2020 11 30;8(1):207. Epub 2020 Nov 30.

Institute of Clinical Neuroimmunology, Biomedical Center and University Hospitals, Ludwig-Maximilians-Universität München, Großhaderner Str. 9, 82152, Planegg-Martinsried, Germany.

Autoimmune disorders of the central nervous system (CNS) comprise a broad spectrum of clinical entities. The stratification of patients based on the recognized autoantigen is of great importance for therapy optimization and for concepts of pathogenicity, but for most of these patients, the actual target of their autoimmune response is unknown. Here we investigated oligodendrocyte myelin glycoprotein (OMGP) as autoimmune target, because OMGP is expressed specifically in the CNS and there on oligodendrocytes and neurons. Using a stringent cell-based assay, we detected autoantibodies to OMGP in serum of 8/352 patients with multiple sclerosis, 1/28 children with acute disseminated encephalomyelitis and unexpectedly, also in one patient with psychosis, but in none of 114 healthy controls. Since OMGP is GPI-anchored, we validated its recognition also in GPI-anchored form. The autoantibodies to OMGP were largely IgG1 with a contribution of IgG4, indicating cognate T cell help. We found high levels of soluble OMGP in human spinal fluid, presumably due to shedding of the GPI-linked OMGP. Analyzing the pathogenic relevance of autoimmunity to OMGP in an animal model, we found that OMGP-specific T cells induce a novel type of experimental autoimmune encephalomyelitis dominated by meningitis above the cortical convexities. This unusual localization may be directed by intrathecal uptake and presentation of OMGP by meningeal phagocytes. Together, OMGP-directed autoimmunity provides a new element of heterogeneity, helping to improve the stratification of patients for diagnostic and therapeutic purposes.
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http://dx.doi.org/10.1186/s40478-020-01086-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7706210PMC
November 2020

Extrinsic immune cell-derived, but not intrinsic oligodendroglial factors contribute to oligodendroglial differentiation block in multiple sclerosis.

Acta Neuropathol 2020 11 7;140(5):715-736. Epub 2020 Sep 7.

Institute of Neuropathology, University Hospital Münster, Pottkamp 2, 48149, Münster, Germany.

Multiple sclerosis (MS) is the most frequent demyelinating disease in young adults and despite significant advances in immunotherapy, disease progression still cannot be prevented. Promotion of remyelination, an endogenous repair mechanism resulting in the formation of new myelin sheaths around demyelinated axons, represents a promising new treatment approach. However, remyelination frequently fails in MS lesions, which can in part be attributed to impaired differentiation of oligodendroglial progenitor cells into mature, myelinating oligodendrocytes. The reasons for impaired oligodendroglial differentiation and defective remyelination in MS are currently unknown. To determine whether intrinsic oligodendroglial factors contribute to impaired remyelination in relapsing-remitting MS (RRMS), we compared induced pluripotent stem cell-derived oligodendrocytes (hiOL) from RRMS patients and controls, among them two monozygous twin pairs discordant for MS. We found that hiOL from RRMS patients and controls were virtually indistinguishable with respect to remyelination-associated functions and proteomic composition. However, while analyzing the effect of extrinsic factors we discovered that supernatants of activated peripheral blood mononuclear cells (PBMCs) significantly inhibit oligodendroglial differentiation. In particular, we identified CD4 T cells as mediators of impaired oligodendroglial differentiation; at least partly due to interferon-gamma secretion. Additionally, we observed that blocked oligodendroglial differentiation induced by PBMC supernatants could not be restored by application of oligodendroglial differentiation promoting drugs, whereas treatment of PBMCs with the immunomodulatory drug teriflunomide prior to supernatant collection partly rescued oligodendroglial differentiation. In summary, these data indicate that the oligodendroglial differentiation block is not due to intrinsic oligodendroglial factors but rather caused by the inflammatory environment in RRMS lesions which underlines the need for drug screening approaches taking the inflammatory environment into account. Combined, these findings may contribute to the development of new remyelination promoting strategies.
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http://dx.doi.org/10.1007/s00401-020-02217-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7547031PMC
November 2020

Lesion stage-dependent causes for impaired remyelination in MS.

Acta Neuropathol 2020 09 24;140(3):359-375. Epub 2020 Jul 24.

Institut für Neuropathologie, Universitätsklinikum Münster, Pottkamp 2, 48149, Münster, Germany.

Multiple sclerosis (MS) is the most frequent demyelinating disease and a leading cause for disability in young adults. Despite significant advances in immunotherapies in recent years, disease progression still cannot be prevented. Remyelination, meaning the formation of new myelin sheaths after a demyelinating event, can fail in MS lesions. Impaired differentiation of progenitor cells into myelinating oligodendrocytes may contribute to remyelination failure and, therefore, the development of pharmacological approaches which promote oligodendroglial differentiation and by that remyelination, represents a promising new treatment approach. However, this generally accepted concept has been challenged recently. To further understand mechanisms contributing to remyelination failure in MS, we combined detailed histological analyses assessing oligodendroglial cell numbers, presence of remyelination as well as the inflammatory environment in different MS lesion types in white matter with in vitro experiments using induced-pluripotent stem cell (iPSC)-derived oligodendrocytes (hiOL) and supernatants from polarized human microglia. Our findings suggest that there are multiple reasons for remyelination failure in MS which are dependent on lesion stage. These include lack of myelin sheath formation despite the presence of mature oligodendrocytes in a subset of active lesions as well as oligodendroglial loss and a hostile tissue environment in mixed active/inactive lesions. Therefore, we conclude that better in vivo and in vitro models which mimic the pathological hallmarks of the different MS lesion types are required for the successful development of remyelination promoting drugs.
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http://dx.doi.org/10.1007/s00401-020-02189-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7424408PMC
September 2020

Tissue-resident memory T cells invade the brain parenchyma in multiple sclerosis white matter lesions.

Brain 2020 06;143(6):1714-1730

Department of Neuroimmunology, Netherlands Institute for Neuroscience, Amsterdam, The Netherlands.

Multiple sclerosis is a chronic inflammatory, demyelinating disease, although it has been suggested that in the progressive late phase, inflammatory lesion activity declines. We recently showed in the Netherlands Brain Bank multiple sclerosis-autopsy cohort considerable ongoing inflammatory lesion activity also at the end stage of the disease, based on microglia/macrophage activity. We have now studied the role of T cells in this ongoing inflammatory lesion activity in chronic multiple sclerosis autopsy cases. We quantified T cells and perivascular T-cell cuffing at a standardized location in the medulla oblongata in 146 multiple sclerosis, 20 neurodegenerative control and 20 non-neurological control brain donors. In addition, we quantified CD3+, CD4+, and CD8+ T cells in 140 subcortical white matter lesions. The location of CD8+ T cells in either the perivascular space or the brain parenchyma was determined using CD8/laminin staining and confocal imaging. Finally, we analysed CD8+ T cells, isolated from fresh autopsy tissues from subcortical multiple sclerosis white matter lesions (n = 8), multiple sclerosis normal-appearing white matter (n = 7), and control white matter (n = 10), by flow cytometry. In normal-appearing white matter, the number of T cells was increased compared to control white matter. In active and mixed active/inactive lesions, the number of T cells was further augmented compared to normal-appearing white matter. Active and mixed active/inactive lesions were enriched for both CD4+ and CD8+ T cells, the latter being more abundant in all lesion types. Perivascular clustering of T cells in the medulla oblongata was only found in cases with a progressive disease course and correlated with a higher percentage of mixed active/inactive lesions and a higher lesion load compared to cases without perivascular clusters in the medulla oblongata. In all white matter samples, CD8+ T cells were located mostly in the perivascular space, whereas in mixed active/inactive lesions, 16.3% of the CD8+ T cells were encountered in the brain parenchyma. CD8+ T cells from mixed active/inactive lesions showed a tissue-resident memory phenotype with expression of CD69, CD103, CD44, CD49a, and PD-1 and absence of S1P1. They upregulated markers for homing (CXCR6), reactivation (Ki-67), and cytotoxicity (GPR56), yet lacked the cytolytic enzyme granzyme B. These data show that in chronic progressive multiple sclerosis cases, inflammatory lesion activity and demyelinated lesion load is associated with an increased number of T cells clustering in the perivascular space. Inflammatory active multiple sclerosis lesions are populated by CD8+ tissue-resident memory T cells, which show signs of reactivation and infiltration of the brain parenchyma.
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http://dx.doi.org/10.1093/brain/awaa117DOI Listing
June 2020

Integrated single cell analysis of blood and cerebrospinal fluid leukocytes in multiple sclerosis.

Nat Commun 2020 01 14;11(1):247. Epub 2020 Jan 14.

Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Münster, Germany.

Cerebrospinal fluid (CSF) protects the central nervous system (CNS) and analyzing CSF aids the diagnosis of CNS diseases, but our understanding of CSF leukocytes remains superficial. Here, using single cell transcriptomics, we identify a specific location-associated composition and transcriptome of CSF leukocytes. Multiple sclerosis (MS) - an autoimmune disease of the CNS - increases transcriptional diversity in blood, but increases cell type diversity in CSF including a higher abundance of cytotoxic phenotype T helper cells. An analytical approach, named cell set enrichment analysis (CSEA) identifies a cluster-independent increase of follicular (TFH) cells potentially driving the known expansion of B lineage cells in the CSF in MS. In mice, TFH cells accordingly promote B cell infiltration into the CNS and the severity of MS animal models. Immune mechanisms in MS are thus highly compartmentalized and indicate ongoing local T/B cell interaction.
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http://dx.doi.org/10.1038/s41467-019-14118-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6959356PMC
January 2020

CD8 T cell-mediated endotheliopathy is a targetable mechanism of neuro-inflammation in Susac syndrome.

Nat Commun 2019 12 18;10(1):5779. Epub 2019 Dec 18.

Institute of Clinical Neuroimmunology, Biomedical Center and Hospital of the Ludwig-Maximilians-University Munich, Großhaderner Straße 9, Martinsried, 82152, Munich, Germany.

Neuroinflammation is often associated with blood-brain-barrier dysfunction, which contributes to neurological tissue damage. Here, we reveal the pathophysiology of Susac syndrome (SuS), an enigmatic neuroinflammatory disease with central nervous system (CNS) endotheliopathy. By investigating immune cells from the blood, cerebrospinal fluid, and CNS of SuS patients, we demonstrate oligoclonal expansion of terminally differentiated activated cytotoxic CD8 T cells (CTLs). Neuropathological data derived from both SuS patients and a newly-developed transgenic mouse model recapitulating the disease indicate that CTLs adhere to CNS microvessels in distinct areas and polarize granzyme B, which most likely results in the observed endothelial cell injury and microhemorrhages. Blocking T-cell adhesion by anti-α4 integrin-intervention ameliorates the disease in the preclinical model. Similarly, disease severity decreases in four SuS patients treated with natalizumab along with other therapy. Our study identifies CD8 T-cell-mediated endotheliopathy as a key disease mechanism in SuS and highlights therapeutic opportunities.
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http://dx.doi.org/10.1038/s41467-019-13593-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6920411PMC
December 2019

Stem cell derived oligodendrocytes to study myelin diseases.

Glia 2020 04 21;68(4):705-720. Epub 2019 Oct 21.

Institute of Neuropathology, University Hospital Münster, Münster, Germany.

Oligodendroglial pathology is central to de- and dysmyelinating, but also contributes to neurodegenerative and psychiatric diseases as well as brain injury. The understanding of oligodendroglial biology in health and disease has been significantly increased during recent years by experimental in vitro and in vivo preclinical studies as well as histological analyses of human tissue samples. However, for many of these diseases the underlying pathology is still not fully understood and treatment options are frequently lacking. This is at least partly caused by the limited access to human oligodendrocytes from patients to perform functional studies and drug screens. The induced pluripotent stem cell technology (iPSC) represents a possibility to circumvent this obstacle and paves new ways to study human disease and to develop new treatment options for so far incurable central nervous system (CNS) diseases. In this review, we summarize the differences between human and rodent oligodendrocytes, provide an overview of the different techniques to generate oligodendrocytes from human progenitor or stem cells and describe the results from studies using iPSC derived oligodendroglial lineage cells. Furthermore, we discuss future perspectives and challenges of the iPSC technology with respect to disease modeling, drug screen, and cell transplantation approaches.
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http://dx.doi.org/10.1002/glia.23733DOI Listing
April 2020

Central nervous system regeneration is driven by microglia necroptosis and repopulation.

Nat Neurosci 2019 07 10;22(7):1046-1052. Epub 2019 Jun 10.

Medical Research Council Centre for Reproductive Health, The Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, UK.

Failed regeneration of CNS myelin contributes to clinical decline in neuroinflammatory and neurodegenerative diseases, for which there is an unmet therapeutic need. Here we reveal that efficient remyelination requires death of proinflammatory microglia followed by repopulation to a pro-regenerative state. We propose that impaired microglia death and/or repopulation may underpin dysregulated microglia activation in neurological diseases, and we reveal therapeutic targets to promote white matter regeneration.
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http://dx.doi.org/10.1038/s41593-019-0418-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6597360PMC
July 2019

TMEM10 Promotes Oligodendrocyte Differentiation and is Expressed by Oligodendrocytes in Human Remyelinating Multiple Sclerosis Plaques.

Sci Rep 2019 03 5;9(1):3606. Epub 2019 Mar 5.

Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, 3801 University St., Montreal, Quebec, H3A 2B4, Canada.

Oligodendrocyte precursor cells (OPCs) differentiate during postnatal development into myelin-forming oligodendrocytes, in a process distinguished by substantial changes in morphology and the onset of myelin gene expression. A mammalian-specific CNS myelin gene, tmem10, also called Opalin, encodes a type 1 transmembrane protein that is highly upregulated during early stages of OPC differentiation; however, a function for TMEM10 has not yet been identified. Here, consistent with previous studies, we detect TMEM10 protein in mouse brain beginning at ~P10 and show that protein levels continue to increase as oligodendrocytes differentiate and myelinate axons in vivo. We show that constitutive TMEM10 overexpression in the Oli-neu oligodendroglial cell line promotes the expression of the myelin-associated genes MAG, CNP and CGT, whereas TMEM10 knock down in primary OPCs reduces CNP mRNA expression and decreases the percentage of MBP-positive oligodendrocytes that differentiate in vitro. Ectopic TMEM10 expression evokes an increase in process extension and branching, and blocking endogenous TMEM10 expression results in oligodendrocytes with abnormal cell morphology. These findings may have implications for human demyelinating disorders, as oligodendrocytes expressing TMEM10 are detected in human remyelinating multiple sclerosis lesions. Together, our findings provide evidence that TMEM10 promotes oligodendrocyte terminal differentiation and may represent a novel target to promote remyelination in demyelinating disorders.
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http://dx.doi.org/10.1038/s41598-019-40342-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6400977PMC
March 2019

Association between pathological and MRI findings in multiple sclerosis.

Lancet Neurol 2019 02;18(2):198-210

Neuroimaging Research Unit and Department of Neurology, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy.

Pathological evaluation is the gold standard for identifying processes related to multiple sclerosis that explain disease manifestations, and for guiding the development of new treatments. However, there are limitations to the techniques used, including the small number of donors available, samples often representing uncommon cases, and impossibility of follow-up. Correlative studies have demonstrated that MRI is sensitive to the different pathological substrates of multiple sclerosis (inflammation, demyelination, and neuro-axonal loss). The role of MRI in evaluating other pathological processes, such as leptomeningeal involvement, central vein and rim of lesions, microstructural abnormalities, iron accumulation, and recovery mechanisms, has been investigated. Although techniques used for quantifying pathological processes in different regions of the CNS have advanced diagnosis and monitoring of disease course and treatment of multiple sclerosis, new perspectives and questions have emerged, including how different pathological processes interact over the disease course and when remyelination might occur. Addressing these questions will require longitudinal studies using MRI in large cohorts of patients with different phenotypes.
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http://dx.doi.org/10.1016/S1474-4422(18)30451-4DOI Listing
February 2019

The K -channel TASK1 affects Oligodendroglial differentiation but not myelin restoration.

Glia 2019 05 9;67(5):870-883. Epub 2019 Jan 9.

Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Münster, Germany.

In multiple sclerosis, demyelination occurs as a consequence of chronic autoimmunity in the central nervous system causing progressive neurological impairment in patients. After a demyelinating event, new myelin sheaths are formed by adult oligodendroglial progenitor cells; a process called remyelination. However, remyelination often fails in multiple sclerosis due to insufficient recruitment and differentiation of oligodendroglial precursor cells. A pivotal role for the two-pore-domain potassium (K ) channel, TASK1, has already been proven for an animal model of multiple sclerosis. However, the mechanisms underlying the TASK1-mediated effects are still elusive. Here, we tested the role of TASK1 channels in oligodendroglial differentiation and remyelination after cuprizone-induced demyelination in male mice. We found TASK1 channels to be functionally expressed on primary murine and human, pluripotent stem cell-derived oligodendrocytes. Lack of TASK1 channels resulted in an increase of mature oligodendrocytes in vitro as well as a higher number of mature oligodendrocytes and accelerated developmental myelination in vivo. Mechanistically, Task1-deficient cells revealed a higher amount of phosphorylated WNK1, a kinase known to be involved in the downstream signaling of the myelination regulator LINGO-1. Furthermore, we analyzed the effect of genetic TASK1 ablation or pharmacological TASK1 inhibition on disease-related remyelination. Neither channel inhibition nor lack of TASK1 channels promoted remyelination after pathological demyelination. In summary, we conclude that functional TASK1 channels participate in the modulation of differentiating oligodendroglial cells in a previously unknown manner. However, while being involved in developmental myelination our data suggest that TASK1 channels have no major effect on remyelination.
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http://dx.doi.org/10.1002/glia.23577DOI Listing
May 2019

Interferon β-Mediated Protective Functions of Microglia in Central Nervous System Autoimmunity.

Int J Mol Sci 2019 Jan 7;20(1). Epub 2019 Jan 7.

Department of Psychiatry and Psychotherapy, University of Münster, 48149 Münster, Germany.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) leading to demyelination and axonal damage. It often affects young adults and can lead to neurological disability. Interferon β (IFNβ) preparations represent widely used treatment regimens for patients with relapsing-remitting MS (RRMS) with therapeutic efficacy in reducing disease progression and frequency of acute exacerbations. In mice, IFNβ therapy has been shown to ameliorate experimental autoimmune encephalomyelitis (EAE), an animal model of MS while genetic deletion of IFNβ or its receptor augments clinical severity of disease. However, the complex mechanism of action of IFNβ in CNS autoimmunity has not been fully elucidated. Here, we review our current understanding of the origin, phenotype, and function of microglia and CNS immigrating macrophages in the pathogenesis of MS and EAE. In addition, we highlight the emerging roles of microglia as IFNβ-producing cells and vice versa the impact of IFNβ on microglia in CNS autoimmunity. We finally discuss recent progress in unraveling the underlying molecular mechanisms of IFNβ-mediated effects in EAE.
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http://dx.doi.org/10.3390/ijms20010190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6337097PMC
January 2019

The guanine nucleotide exchange factor Vav3 modulates oligodendrocyte precursor differentiation and supports remyelination in white matter lesions.

Glia 2019 02 18;67(2):376-392. Epub 2018 Nov 18.

Department of Cell Morphology and Molecular Neurobiology, Ruhr-University Bochum, Germany.

The tightly controlled processes of myelination and remyelination require the participation of the cytoskeleton. The reorganization of the cytoskeleton is controlled by small GTPases of the RhoA family. Here, we report that Vav3, a Rho GTPase regulating guanine nucleotide exchange factor (GEF) is involved in oligodendrocyte maturation, myelination and remyelination. When Vav3 was eliminated by genetic recombination, oligodendrocyte precursor cell (OPC) differentiation toward mature oligodendrocytes was accelerated. In contrast, Vav3-deficient oligodendrocytes displayed a reduced capacity to myelinate synthetic microfibers in vitro. Furthermore, remyelination was impaired in Vav3 knockout cerebellar slice cultures that were demyelinated by the addition of lysolecithin. In agreement with these observations, remyelination was compromised when the cuprizone model of myelin lesion was performed in Vav3-deficient mice. When Vav3-deficient oligodendrocytes were examined with Förster resonance energy transfer (FRET)-based biosensors, an altered activation profile of RhoA GTPases was revealed on the cellular level, which could be responsible for an impaired remyelination. Taken together, this study highlights Vav3 as a novel regulator of oligodendrocyte maturation and remyelination, suggesting that manipulation of the Vav3-dependent signaling pathway could help to improve myelin repair.
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http://dx.doi.org/10.1002/glia.23548DOI Listing
February 2019

Oligodendroglial α-synucleinopathy-driven neuroinflammation in multiple system atrophy.

Brain Pathol 2019 05 31;29(3):380-396. Epub 2019 Jan 31.

Department of Molecular Neurology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.

Neuroinflammation and oligodendroglial cytoplasmic α-synuclein (α-syn) inclusions (GCIs) are important neuropathological characteristics of multiple system atrophy (MSA). GCIs are known to interfere with oligodendroglial maturation and consequently result in myelin loss. The neuroinflammatory phenotype in the context of MSA, however, remains poorly understood. Here, we demonstrate MSA-associated neuroinflammation being restricted to myeloid cells and tightly linked to oligodendroglial α-syncleinopathy. In human putaminal post-mortem tissue of MSA patients, neuroinflammation was observed in white matter regions only. This locally restricted neuroinflammation coincided with elevated numbers of α-syn inclusions, while gray matter with less α-synucleinopathy remained unaffected. In order to analyze the temporal pattern of neuroinflammation, a transgenic mouse model overexpressing human α-syn under the control of an oligodendrocyte-specific myelin basic protein (MBP) promoter (MBP29-hα-syn mice) was assessed in a pre-symptomatic and symptomatic disease stage. Strikingly, we detected an increased neuroinflammation in regions with a high α-syn load, the corpus callosum and the striatum, of MBP29-hα-syn mice, already at a pre-symptomatic stage. Furthermore, this inflammatory response was restricted to myeloid cells being highly proliferative and showing an activated, phagocytic phenotype. In contrast, severe astrogliosis was observed only in gray matter regions of MSA patients as well as MBP29-hα-syn mice. To further characterize the influence of oligodendrocytes on initiation of the myeloid immune response, we performed RNA sequencing analysis of α-syn overexpressing primary oligodendrocytes. A distinct gene expression profile including upregulation of cytokines important for myeloid cell attraction and proliferation was detected in α-syn overexpressing oligodendrocytes. Additionally, microdissected tissue of MBP29-hα-syn mice exhibited a similar cellular gene expression profile in white matter regions even pre-symptomatically. Collectively, these results imply an early crosstalk between neuroinflammation and oligodendrocytes containing α-syn inclusions leading to an immune response locally restricted to white matter regions in MSA.
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http://dx.doi.org/10.1111/bpa.12678DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6850330PMC
May 2019

Publisher Correction: Maladaptive cortical hyperactivity upon recovery from experimental autoimmune encephalomyelitis.

Nat Neurosci 2019 Jan;22(1):144

Focus Program Translational Neurosciences & Institute of Pathophysiology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.

In the version of this article initially published, Inigo Ruiz de Azua's name was miscategorized. His given name is Inigo and his surname is Ruiz de Azua. This has been corrected in the HTML coding.
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http://dx.doi.org/10.1038/s41593-018-0274-2DOI Listing
January 2019

Maladaptive cortical hyperactivity upon recovery from experimental autoimmune encephalomyelitis.

Nat Neurosci 2018 10 26;21(10):1392-1403. Epub 2018 Sep 26.

Focus Program Translational Neurosciences & Institute of Pathophysiology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.

Multiple sclerosis (MS) patients exhibit neuropsychological symptoms in early disease despite the immune attack occurring predominantly in white matter and spinal cord. It is unclear why neurodegeneration may start early in the disease and is prominent in later stages. We assessed cortical microcircuit activity by employing spiking-specific two-photon Ca imaging in proteolipid protein-immunized relapsing-remitting SJL/J mice in vivo. We identified the emergence of hyperactive cortical neurons in remission only, independent of direct immune-mediated damage and paralleled by elevated anxiety. High levels of neuronal activity were accompanied by increased caspase-3 expression. Cortical TNFα expression was mainly increased by excitatory neurons in remission; blockade with intraventricular infliximab restored AMPA spontaneous excitatory postsynaptic current frequencies, completely recovered normal neuronal network activity patterns and alleviated elevated anxiety. This suggests a dysregulation of cortical networks attempting to achieve functional compensation by synaptic plasticity mechanisms, indicating a link between immune attack and early start of neurodegeneration.
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http://dx.doi.org/10.1038/s41593-018-0193-2DOI Listing
October 2018

ALK3 undergoes ligand-independent homodimerization and BMP-induced heterodimerization with ALK2.

Free Radic Biol Med 2018 12 15;129:127-137. Epub 2018 Sep 15.

Department of Anesthesiology, Intensive Care and Pain Medicine, University Hospital Muenster, University of Muenster, Muenster, Germany. Electronic address:

The bone morphogenetic protein (BMP) type I receptors ALK2 and ALK3 are essential for expression of hepcidin, a key iron regulatory hormone. In mice, hepatocyte-specific Alk2 deficiency leads to moderate iron overload with periportal liver iron accumulation, while hepatocyte-specific Alk3 deficiency leads to severe iron overload with centrilobular liver iron accumulation and a more marked reduction of basal hepcidin levels. The objective of this study was to investigate whether the two receptors have additive roles in hepcidin regulation. Iron overload in mice with hepatocyte-specific Alk2 and Alk3 (Alk2/3) deficiency was characterized and compared to hepatocyte-specific Alk3 deficient mice. Co-immunoprecipitation studies were performed to detect the formation of ALK2 and ALK3 homodimer and heterodimer complexes in vitro in the presence and absence of ligands. The iron overload phenotype of hepatocyte-specific Alk2/3-deficient mice was more severe than that of hepatocyte-specific Alk3-deficient mice. In vitro co-immunoprecipitation studies in Huh7 cells showed that ALK3 can homodimerize in absence of BMP2 or BMP6. In contrast, ALK2 did not homodimerize in either the presence or absence of BMP ligands. However, ALK2 did form heterodimers with ALK3 in the presence of BMP2 or BMP6. ALK3-ALK3 and ALK2-ALK3 receptor complexes induced hepcidin expression in Huh7 cells. Our data indicate that: (I) ALK2 and ALK3 have additive functions in vivo, as Alk2/3 deficiency leads to a greater degree of iron overload than Alk3 deficiency; (II) ALK3, but not ALK2, undergoes ligand-independent homodimerization; (III) the formation of ALK2-ALK3 heterodimers is ligand-dependent and (IV) both receptor complexes functionally induce hepcidin expression in vitro.
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http://dx.doi.org/10.1016/j.freeradbiomed.2018.09.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6842210PMC
December 2018

Blockade of MCAM/CD146 impedes CNS infiltration of T cells over the choroid plexus.

J Neuroinflammation 2018 Aug 22;15(1):236. Epub 2018 Aug 22.

Clinic of Neurology with Institute of Translational Neurology, University of Münster, Albert-Schweitzer-Campus-1, Building A01, 48149, Münster, Germany.

Background: Very late antigen 4 (VLA-4; integrin α4β1) is critical for transmigration of T helper (T) 1 cells into the central nervous system (CNS) under inflammatory conditions such as multiple sclerosis (MS). We have previously shown that VLA-4 and melanoma cell adhesion molecule (MCAM) are important for trans-endothelial migration of human T17 cells in vitro and here investigate their contribution to pathogenic CNS inflammation.

Methods: Antibody blockade of VLA-4 and MCAM is assessed in murine models of CNS inflammation in conjunction with conditional ablation of α4-integrin expression in T cells. Effects of VLA-4 and MCAM blockade on lymphocyte migration are further investigated in the human system via in vitro T cell transmigration assays.

Results: Compared to the broad effects of VLA-4 blockade on encephalitogenic T cell migration over endothelial barriers, MCAM blockade impeded encephalitogenic T cell migration in murine models of MS that especially depend on CNS migration across the choroid plexus (CP). In transgenic mice lacking T cell α4-integrin expression (CD4::Itga4), MCAM blockade delayed disease onset. Migration of MCAM-expressing T cells through the CP into the CNS was restricted, where laminin 411 (composed of α4, β1, γ1 chains), the proposed major ligand of MCAM, is detected in the endothelial basement membranes of murine CP tissue. This finding was translated to the human system; blockade of MCAM with a therapeutic antibody reduced in vitro transmigration of MCAM-expressing T cells across a human fibroblast-derived extracellular matrix layer and a brain-derived endothelial monolayer, both expressing laminin α4. Laminin α4 was further detected in situ in CP endothelial-basement membranes in MS patients' brain tissue.

Conclusions: Our findings suggest that MCAM-laminin 411 interactions facilitate trans-endothelial migration of MCAM-expressing T cells into the CNS, which seems to be highly relevant to migration via the CP and to potential future clinical applications in neuroinflammatory disorders.
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http://dx.doi.org/10.1186/s12974-018-1276-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6106934PMC
August 2018

Nur77 serves as a molecular brake of the metabolic switch during T cell activation to restrict autoimmunity.

Proc Natl Acad Sci U S A 2018 08 2;115(34):E8017-E8026. Epub 2018 Aug 2.

Department of Neurology with Institute of Translational Neurology, University Hospital Muenster, 48149 Muenster, Germany;

T cells critically depend on reprogramming of metabolic signatures to meet the bioenergetic demands during activation and clonal expansion. Here we identify the transcription factor Nur77 as a cell-intrinsic modulator of T cell activation. Nur77-deficient T cells are highly proliferative, and lack of Nur77 is associated with enhanced T cell activation and increased susceptibility for T cell-mediated inflammatory diseases, such as CNS autoimmunity, allergic contact dermatitis and collagen-induced arthritis. Importantly, Nur77 serves as key regulator of energy metabolism in T cells, restricting mitochondrial respiration and glycolysis and controlling switching between different energy pathways. Transcriptional network analysis revealed that Nur77 modulates the expression of metabolic genes, most likely in close interaction with other transcription factors, especially estrogen-related receptor α. In summary, we identify Nur77 as a transcriptional regulator of T cell metabolism, which elevates the threshold for T cell activation and confers protection in different T cell-mediated inflammatory diseases.
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http://dx.doi.org/10.1073/pnas.1721049115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6112725PMC
August 2018

Protective potential of dimethyl fumarate in a mouse model of thalamocortical demyelination.

Brain Struct Funct 2018 Sep 9;223(7):3091-3106. Epub 2018 May 9.

Institute of Physiology I, Westfälische Wilhelms-University, Robert-Koch-Str. 27a, 48149, Münster, Germany.

Alterations in cortical cellular organization, network functionality, as well as cognitive and locomotor deficits were recently suggested to be pathological hallmarks in multiple sclerosis and corresponding animal models as they might occur following demyelination. To investigate functional changes following demyelination in a well-defined, topographically organized neuronal network, in vitro and in vivo, we focused on the primary auditory cortex (A1) of mice in the cuprizone model of general de- and remyelination. Following myelin loss in this model system, the spatiotemporal propagation of incoming stimuli in A1 was altered and the hierarchical activation of supra- and infragranular cortical layers was lost suggesting a profound effect exerted on neuronal network level. In addition, the response latency in field potential recordings and voltage-sensitive dye imaging was increased following demyelination. These alterations were accompanied by a loss of auditory discrimination abilities in freely behaving animals, a reduction of the nuclear factor-erythroid 2-related factor-2 (Nrf-2) protein in the nucleus in histological staining and persisted during remyelination. To find new strategies to restore demyelination-induced network alteration in addition to the ongoing remyelination, we tested the cytoprotective potential of dimethyl fumarate (DMF). Therapeutic treatment with DMF during remyelination significantly modified spatiotemporal stimulus propagation in the cortex, reduced the cognitive impairment, and prevented the demyelination-induced decrease in nuclear Nrf-2. These results indicate the involvement of anti-oxidative mechanisms in regulating spatiotemporal cortical response pattern following changes in myelination and point to DMF as therapeutic compound for intervention.
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http://dx.doi.org/10.1007/s00429-018-1680-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6132667PMC
September 2018

Publisher Correction: Nfat/calcineurin signaling promotes oligodendrocyte differentiation and myelination by transcription factor network tuning.

Nat Commun 2018 04 23;9(1):1667. Epub 2018 Apr 23.

Institut für Biochemie, Emil-Fischer-Zentrum, Friedrich-Alexander-Universität Erlangen-Nürnberg, D-91054, Erlangen, Germany.

The originally published version of this Article omitted Tanja Kuhlmann and Michael Wegner as jointly supervising authors. This has now been corrected in both the PDF and HTML versions of the Article.
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http://dx.doi.org/10.1038/s41467-018-03871-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5913303PMC
April 2018

Nfat/calcineurin signaling promotes oligodendrocyte differentiation and myelination by transcription factor network tuning.

Nat Commun 2018 03 2;9(1):899. Epub 2018 Mar 2.

Institut für Biochemie, Emil-Fischer-Zentrum, Friedrich-Alexander-Universität Erlangen-Nürnberg, D-91054, Erlangen, Germany.

Oligodendrocytes produce myelin for rapid transmission and saltatory conduction of action potentials in the vertebrate central nervous system. Activation of the myelination program requires several transcription factors including Sox10, Olig2, and Nkx2.2. Functional interactions among them are poorly understood and important components of the regulatory network are still unknown. Here, we identify Nfat proteins as Sox10 targets and regulators of oligodendroglial differentiation in rodents and humans. Overall levels and nuclear fraction increase during differentiation. Inhibition of Nfat activity impedes oligodendrocyte differentiation in vitro and in vivo. On a molecular level, Nfat proteins cooperate with Sox10 to relieve reciprocal repression of Olig2 and Nkx2.2 as precondition for oligodendroglial differentiation and myelination. As Nfat activity depends on calcium-dependent activation of calcineurin signaling, regulatory network and oligodendroglial differentiation become sensitive to calcium signals. NFAT proteins are also detected in human oligodendrocytes, downregulated in active multiple sclerosis lesions and thus likely relevant in demyelinating disease.
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http://dx.doi.org/10.1038/s41467-018-03336-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5834605PMC
March 2018

Deficiency of the BMP Type I receptor ALK3 partly protects mice from anemia of inflammation.

BMC Physiol 2018 Feb 27;18(1). Epub 2018 Feb 27.

Department of Anaesthesiology, Intensive Care and Pain Medicine, University Hospital Muenster, Albert-Schweitzer Campus 1, Building A1, 48149, Muenster, Germany.

Background: Inflammatory stimuli induce the hepatic iron regulatory hormone hepcidin, which contributes to anaemia of inflammation (AI). Hepcidin expression is regulated by the bone morphogenetic protein (BMP) and the interleukin-6 (IL-6) signalling pathways. Prior results indicate that the BMP type I receptor ALK3 is mainly involved in the acute inflammatory hepcidin induction four and 72 h after IL-6 administration. In this study, the role of ALK3 in a chronic model of inflammation was investigated. The intact, heat-killed bacterium Brucella abortus (BA) was used to analyse its effect on the development of inflammation and hypoferremia in mice with hepatocyte-specific Alk3-deficiency (Alk3; Alb-Cre) compared to control (Alk3) mice.

Results: An iron restricted diet prevented development of the iron overload phenotype in mice with hepatocyte-specific Alk3 deficiency. Regular diet leads to iron overload and increased haemoglobin levels in these mice, which protects from the development of AI per se. Fourteen days after BA injection Alk3; Alb-Cre mice presented milder anaemia (Hb 16.7 g/dl to 11.6 g/dl) compared to Alk3 control mice (Hb 14.9 g/dl to 8.6 g/dl). BA injection led to an intact inflammatory response in all groups of mice. In Alk3; Alb-Cre mice, SMAD1/5/8 phosphorylation was reduced after BA as well as after infection with Staphylococcus aureus. The reduction of the SMAD1/5/8 signalling pathway due to hepatocyte-specific Alk3 deficiency partly suppressed the induction of STAT3 signalling.

Conclusion: The results reveal in vivo, that 1) hepatocyte-specific Alk3 deficiency partly protects from AI, 2) the development of hypoferremia is partly dependent on ALK3, and 3) the ALK3/BMP/hepcidin axis may serve as a possible therapeutic target to attenuate AI.
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http://dx.doi.org/10.1186/s12899-018-0037-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6389079PMC
February 2018