Publications by authors named "Timothy R Crother"

58 Publications

Recruitment of pro-IL-1α to mitochondrial cardiolipin, via shared LC3 binding domain, inhibits mitophagy and drives maximal NLRP3 activation.

Proc Natl Acad Sci U S A 2021 Jan;118(1)

Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048;

The balance between NLRP3 inflammasome activation and mitophagy is essential for homeostasis and cellular health, but this relationship remains poorly understood. Here we found that interleukin-1α (IL-1α)-deficient macrophages have reduced caspase-1 activity and diminished IL-1β release, concurrent with reduced mitochondrial damage, suggesting a role for IL-1α in regulating this balance. LPS priming of macrophages induced pro-IL-1α translocation to mitochondria, where it directly interacted with mitochondrial cardiolipin (CL). Computational modeling revealed a likely CL binding motif in pro-IL-1α, similar to that found in LC3b. Thus, binding of pro-IL-1α to CL in activated macrophages may interrupt CL-LC3b-dependent mitophagy, leading to enhanced Nlrp3 inflammasome activation and more robust IL-1β production. Mutation of pro-IL-1α residues predicted to be involved in CL binding resulted in reduced pro-IL-1α-CL interaction, a reduction in NLRP3 inflammasome activity, and increased mitophagy. These data identify a function for pro-IL-1α in regulating mitophagy and the potency of NLRP3 inflammasome activation.
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http://dx.doi.org/10.1073/pnas.2015632118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7817159PMC
January 2021

Oxidative DNA Damage Accelerates Skin Inflammation in Pristane-Induced Lupus Model.

Front Immunol 2020 24;11:554725. Epub 2020 Sep 24.

Division of Pediatric Infectious Diseases and Immunology, Cedars-Sinai Medical Center, Los Angeles, CA, United States.

Systemic Lupus Erythematosus (SLE) is a chronic inflammatory autoimmune disease in which type I interferons (IFN) play a key role. The IFN response can be triggered when oxidized DNA engages the cytosolic DNA sensing platform cGAS-STING, but the repair mechanisms that modulate this process and govern disease progression are unclear. To gain insight into this biology, we interrogated the role of oxyguanine glycosylase 1 (OGG1), which repairs oxidized guanine 8-Oxo-2'-deoxyguanosine (8-OH-dG), in the pristane-induced mouse model of SLE. mice showed increased influx of Ly6C monocytes into the peritoneal cavity and enhanced IFN-driven gene expression in response to short-term exposure to pristane. Loss of was associated with increased auto-antibodies (anti-dsDNA and anti-RNP), higher total IgG, and expression of interferon stimulated genes (ISG) to longer exposure to pristane, accompanied by aggravated skin pathology such as hair loss, thicker epidermis, and increased deposition of IgG in skin lesions. Supporting a role for type I IFNs in this model, skin lesions of mice had significantly higher expression of type I IFN genes (, and ). In keeping with loss of resulting in dysregulated IFN responses, enhanced basal and cGAMP-dependent expression was observed in BMDMs from mice. Use of the STING inhibitor, H151, reduced both basal and cGAMP-driven increases, indicating that OGG1 regulates expression through the cGAS-STING pathway. Finally, in support for a role for OGG1 in the pathology of cutaneous disease, reduced expression in monocytes associated with skin involvement in SLE patients and the expression of was significantly lower in lesional skin compared with non-lesional skin in patients with Discoid Lupus. Taken together, these data support an important role for OGG1 in protecting against IFN production and SLE skin disease.
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http://dx.doi.org/10.3389/fimmu.2020.554725DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7541920PMC
September 2020

Sex-Specific Effects of the Nlrp3 Inflammasome on Atherogenesis in LDL Receptor-Deficient Mice.

JACC Basic Transl Sci 2020 Jun 20;5(6):582-598. Epub 2020 May 20.

Department of Biomedical Sciences, Infectious and Immunologic Diseases Research Center, Cedars-Sinai Medical Center, Los Angeles, California.

In the mouse model of atherosclerosis, female bone marrow chimera and mice developed significantly smaller lesions in the aortic sinus and decreased lipid content in aorta en face, but a similar protection was not observed in males. Ovariectomized female mice lost protection from atherosclerosis in the setting of NLRP3 deficiency, whereas atherosclerosis showed a greater dependency on NLRP3 in castrated males. Thus, castration increased the dependency of atherosclerosis on the NLRP3 inflammasome, suggesting that testosterone may block inflammation in atherogenesis. Conversely, ovariectomy reduced the dependency on NLRP3 inflammasome components for atherogenesis, suggesting that estrogen may promote inflammasome-mediated atherosclerosis.
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http://dx.doi.org/10.1016/j.jacbts.2020.03.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7315187PMC
June 2020

MD-2 as a possible therapeutic target for atherosclerosis.

EBioMedicine 2020 05 7;55:102760. Epub 2020 May 7.

Department of Pediatrics, Division of Infectious Diseases and Immunology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Department of Biomedical Sciences, Infectious and Immunologic Disease Research Center, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. Electronic address:

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http://dx.doi.org/10.1016/j.ebiom.2020.102760DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7217989PMC
May 2020

Loss of testosterone impairs anti-tumor neutrophil function.

Nat Commun 2020 03 31;11(1):1613. Epub 2020 Mar 31.

Department of Pediatrics, Division of Infectious Diseases and Immunology, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.

In men, the incidence of melanoma rises rapidly after age 50, and nearly two thirds of melanoma deaths are male. The immune system is known to play a key role in controlling the growth and spread of malignancies, but whether age- and sex-dependent changes in immune cell function account for this effect remains unknown. Here, we show that in castrated male mice, neutrophil maturation and function are impaired, leading to elevated metastatic burden in two models of melanoma. Replacement of testosterone effectively normalized the tumor burden in castrated male mice. Further, the aberrant neutrophil phenotype was also observed in prostate cancer patients receiving androgen deprivation therapy, highlighting the evolutionary conservation and clinical relevance of the phenotype. Taken together, these results provide a better understanding of the role of androgen signaling in neutrophil function and the impact of this biology on immune control of malignancies.
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http://dx.doi.org/10.1038/s41467-020-15397-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7109066PMC
March 2020

Autophagy Protects Against Developing Increased Lung Permeability and Hypoxemia by Down Regulating Inflammasome Activity and IL-1β in LPS Plus Mechanical Ventilation-Induced Acute Lung Injury.

Front Immunol 2020 14;11:207. Epub 2020 Feb 14.

Division of Infectious Diseases and Immunology, Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, CA, United States.

Targeting inflammasome activation to modulate interleukin (IL)-1β is a promising treatment strategy against acute respiratory distress syndrome and ventilator-induced lung injury (VILI). Autophagy is a key regulator of inflammasome activation in macrophages. Here, we investigated the role of autophagy in the development of acute lung injury (ALI) induced by lipopolysaccharide (LPS) and mechanical ventilation (MV). Two hours before starting MV, 0.2 mg/kg LPS was administered to mice intratracheally. Mice were then placed on high-volume MV (30 ml/kg with 3 cmHO positive end-expiratory pressure for 2.5 h without additional oxygen application). Mice with myeloid-specific deletion of the autophagic protein ATG16L1 () suffered severe hypoxemia (adjusted < 0.05) and increased lung permeability ( < 0.05, albumin level in bronchoalveolar lavage fluid) with significantly higher IL-1β release into alveolar space ( < 0.05). Induction of autophagy by fasting-induced starvation led to improved arterial oxygenation (adjusted < 0.0001) and lung permeability ( < 0.05), as well as significantly suppressed IL-1β production ( < 0.01). Intratracheal treatment with anti-mouse IL-1β monoclonal antibody (mAb; 2.5 mg/kg) significantly improved arterial oxygenation (adjusted < 0.01) as well as lung permeability ( < 0.05). On the other hand, deletion of IL-1α gene or use of anti-mouse IL-1α mAb (2.5 mg/kg) provided no significant protection, suggesting that the LPS and MV-induced ALI is primarily dependent on IL-1β, but independent of IL-1α. These observations suggest that autophagy has a protective role in controlling inflammasome activation and production of IL-1β, which plays a critical role in developing hypoxemia and increased lung permeability in LPS plus MV-induced acute lung injury.
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http://dx.doi.org/10.3389/fimmu.2020.00207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7033480PMC
March 2021

Intestinal Permeability and IgA Provoke Immune Vasculitis Linked to Cardiovascular Inflammation.

Immunity 2019 09 27;51(3):508-521.e6. Epub 2019 Aug 27.

Division of Pediatric Infectious Diseases and Immunology, Department of Biomedical Sciences, Infectious and Immunologic Diseases Research Center (IIDRC), Cedars-Sinai Medical Center, Los Angeles, CA, USA; Department of Pediatrics, Cedars-Sinai Medical Center, and David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. Electronic address:

Recent experimental data and clinical, genetic, and transcriptome evidence from patients converge to suggest a key role of interleukin-1β (IL-1β) in the pathogenesis of Kawasaki disease (KD). However, the molecular mechanisms involved in the development of cardiovascular lesions during KD vasculitis are still unknown. Here, we investigated intestinal barrier function in KD vasculitis and observed evidence of intestinal permeability and elevated circulating secretory immunoglobulin A (sIgA) in KD patients, as well as elevated sIgA and IgA deposition in vascular tissues in a mouse model of KD vasculitis. Targeting intestinal permeability corrected gut permeability, prevented IgA deposition and ameliorated cardiovascular pathology in the mouse model. Using genetic and pharmacologic inhibition of IL-1β signaling, we demonstrate that IL-1β lies upstream of disrupted intestinal barrier function, subsequent IgA vasculitis development, and cardiac inflammation. Targeting mucosal barrier dysfunction and the IL-1β pathway may also be applicable to other IgA-related diseases, including IgA vasculitis and IgA nephropathy.
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http://dx.doi.org/10.1016/j.immuni.2019.05.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6751009PMC
September 2019

Autophagy Limits Inflammasome During Infection.

Front Immunol 2019 12;10:754. Epub 2019 Apr 12.

Division of Pediatric Infectious Diseases and Immunology, Department of Pediatrics, and Infectious and Immunological Diseases Research Center, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, United States.

Autophagy can either antagonize or promote intracellular bacterial growth, depending on the pathogen. Here, we investigated the role of autophagy during a pulmonary infection with the obligate intracellular pathogen, (CP). In mouse embryonic fibroblasts (MEFs) or macrophages, deficiency of autophagy pathway components led to enhanced CP replication, suggesting that autophagy exerts a bactericidal role. However, , mice with myeloid-specific deletion of the autophagic protein ATG16L1 suffered increased mortality during CP infection, neutrophilia, and increased inflammasome activation despite no change in bacterial burden. Induction of autophagy led to reduced CP replication , but impaired survival in CP-infected mice, associated with an initial reduction in IL-1β production, followed by enhanced neutrophil recruitment, defective CP clearance, and later inflammasome activation and IL-1β production, which drove the resulting mortality. Taken together, our data suggest that a delicate interplay exists between autophagy and inflammasome activation in determining the outcome of CP infection, perturbation of which can result in inflammatory pathology or unrestricted bacterial growth.
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http://dx.doi.org/10.3389/fimmu.2019.00754DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6473188PMC
August 2020

Myocardial fibrosis after adrenergic stimulation as a long-term sequela in a mouse model of Kawasaki disease vasculitis.

JCI Insight 2019 Feb 7;4(3). Epub 2019 Feb 7.

Departments of Biomedical Sciences and Pediatrics, Divisions of Infectious Diseases and Immunology.

Kawasaki disease (KD), the leading cause of acquired cardiac disease among children, is often associated with myocarditis that may lead to long-term myocardial dysfunction and fibrosis. Although those myocardial changes develop during the acute phase, they may persist for decades and closely correlate with long-term myocardial sequelae. Using the Lactobacillus casei cell wall extract-induced (LCWE-induced) KD vasculitis murine model, we investigated long-term cardiovascular sequelae, such as myocardial dysfunction, fibrosis, and coronary microvascular lesions following adrenergic stimuli after established KD vasculitis. We found that adrenergic stimulation with isoproterenol following LCWE-induced KD vasculitis in mice was associated with increased risk of cardiac hypertrophy and myocardial fibrosis, diminished ejection fraction, and increased serum levels of brain natriuretic peptide. Myocardial fibrosis resulting from pharmacologic-induced exercise after KD development was IL-1 signaling dependent and was associated with a significant reduction in myocardial capillary CD31 expression, indicative of a rarefied myocardial capillary bed. These observations suggest that adrenergic stimulation after KD vasculitis may lead to cardiac hypertrophy and bridging fibrosis in the myocardium in the LCWE-induced KD vasculitis mouse model and that this process involves IL-1 signaling and diminished microvascular circulation in the myocardium.
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http://dx.doi.org/10.1172/jci.insight.126279DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6413776PMC
February 2019

T-Cell-Intrinsic Receptor Interacting Protein 2 Regulates Pathogenic T Helper 17 Cell Differentiation.

Immunity 2018 11 23;49(5):873-885.e7. Epub 2018 Oct 23.

Department of Pediatrics, Division of Infectious Diseases and Immunology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Department of Biomedical Sciences, Infectious and Immunologic Disease Research Center, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Department of Biomedical Science, Research Division of Immunology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA. Electronic address:

Receptor interacting protein 2 (RIP2) plays a role in sensing intracellular pathogens, but its function in T cells is unclear. We show that RIP2 deficiency in CD4 T cells resulted in chronic and severe interleukin-17A-mediated inflammation during Chlamydia pneumoniae lung infection, increased T helper 17 (Th17) cell formation in lungs of infected mice, accelerated atherosclerosis, and more severe experimental autoimmune encephalomyelitis. While RIP2 deficiency resulted in reduced conventional Th17 cell differentiation, it led to significantly enhanced differentiation of pathogenic (p)Th17 cells, which was dependent on RORα transcription factor and interleukin-1 but independent of nucleotide oligomerization domain (NOD) 1 and 2. Overexpression of RIP2 resulted in suppression of pTh17 cell differentiation, an effect mediated by its CARD domain, and phenocopied by a cell-permeable RIP2 CARD peptide. Our data suggest that RIP2 has a T cell-intrinsic role in determining the balance between homeostatic and pathogenic Th17 cell responses.
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http://dx.doi.org/10.1016/j.immuni.2018.08.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6260980PMC
November 2018

Expansion of commensal fungus Wallemia mellicola in the gastrointestinal mycobiota enhances the severity of allergic airway disease in mice.

PLoS Pathog 2018 09 20;14(9):e1007260. Epub 2018 Sep 20.

F. Widjaja Foundation Inflammatory Bowel & Immunobiology Research Institute, and the Division of Immunology, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.

The gastrointestinal microbiota influences immune function throughout the body. The gut-lung axis refers to the concept that alterations of gut commensal microorganisms can have a distant effect on immune function in the lung. Overgrowth of intestinal Candida albicans has been previously observed to exacerbate allergic airways disease in mice, but whether subtler changes in intestinal fungal microbiota can affect allergic airways disease is less clear. In this study we have investigated the effects of the population expansion of commensal fungus Wallemia mellicola without overgrowth of the total fungal community. Wallemia spp. are commonly found as a minor component of the commensal gastrointestinal mycobiota in both humans and mice. Mice with an unaltered gut microbiota community resist population expansion when gavaged with W. mellicola; however, transient antibiotic depletion of gut microbiota creates a window of opportunity for expansion of W. mellicola following delivery of live spores to the gastrointestinal tract. This phenomenon is not universal as other commensal fungi (Aspergillus amstelodami, Epicoccum nigrum) do not expand when delivered to mice with antibiotic-depleted microbiota. Mice with Wallemia-expanded gut mycobiota experienced altered pulmonary immune responses to inhaled aeroallergens. Specifically, after induction of allergic airways disease with intratracheal house dust mite (HDM) antigen, mice demonstrated enhanced eosinophilic airway infiltration, airway hyperresponsiveness (AHR) to methacholine challenge, goblet cell hyperplasia, elevated bronchoalveolar lavage IL-5, and enhanced serum HDM IgG1. This phenomenon occurred with no detectable Wallemia in the lung. Targeted amplicon sequencing analysis of the gastrointestinal mycobiota revealed that expansion of W. mellicola in the gut was associated with additional alterations of bacterial and fungal commensal communities. We therefore colonized fungus-free Altered Schaedler Flora (ASF) mice with W. mellicola. ASF mice colonized with W. mellicola experienced enhanced severity of allergic airways disease compared to fungus-free control ASF mice without changes in bacterial community composition.
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http://dx.doi.org/10.1371/journal.ppat.1007260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6147580PMC
September 2018

Circulating monocytes from prostate cancer patients promote invasion and motility of epithelial cells.

Cancer Med 2018 09 9;7(9):4639-4649. Epub 2018 Aug 9.

Urologic Oncology Program/Uro-Oncology Research Laboratories, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.

Background: Recruited myeloid cells are known to promote cancer initiation, malignant progression, metastasis, and resistance to therapy in the tumor niche. We tested the hypothesis that circulating blood monocytes from advanced prostate cancer (PCa) patients exhibit a protumor phenotype and directly influence the tumor microenvironment in response to tumor-derived signals.

Methods: Blood monocytes from advanced and stable PCa patients were cultured, and the conditioned media (CM) were collected and analyzed using standard invasion and wound closure assays to measure effects on invasion and motility of PCa tumor cells. We then identified the proteome profile of these monocytes using proteome array and ELISA.

Results: Conditioned media from circulating monocytes in patients with metastatic prostate cancer (PCa-M) increased invasion of epithelial PCa cells in vitro. Proteome Profiler Analysis revealed that monocyte-derived CM from metastatic castration-resistant (mCRPC) patients presented high levels of chitinase-3-like 1 (CHI3L1, YKL-40) when compared to patients with stable disease (PCa-N) and healthy control individuals (HC). The only described receptor for CHI3L1, interleukin-13 receptor α2 (IL-13Rα2), was significantly up-regulated in the human metastatic PCa cell line, ARCaP . Accordingly, we observed that the activation of IL-13Rα2 from PCa-M CM increased the invasiveness of ARCaP cells while siRNA directed against this receptor significantly reduced invasiveness of these cells in the presence of CM from PCa-M patients.

Conclusions: Thus, we show that circulating monocytes from metastatic PCa patients exert a tumor-promoting role via the secretion of CHI3L1, and CHI3L1 demands further exploration as a possible therapeutic target in advanced PCa.
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http://dx.doi.org/10.1002/cam4.1695DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6143932PMC
September 2018

Chlamydia pneumoniae Hijacks a Host Autoregulatory IL-1β Loop to Drive Foam Cell Formation and Accelerate Atherosclerosis.

Cell Metab 2018 09 21;28(3):432-448.e4. Epub 2018 Jun 21.

Departments of Pediatrics and Medicine, Division of Infectious Diseases and Immunology, and Infectious and Immunologic Diseases Research Center (IIDRC), Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.

Pathogen burden accelerates atherosclerosis, but the mechanisms remain unresolved. Activation of the NLRP3 inflammasome is linked to atherogenesis. Here we investigated whether Chlamydia pneumoniae (C.pn) infection engages NLRP3 in promoting atherosclerosis. C.pn potentiated hyperlipidemia-induced inflammasome activity in cultured macrophages and in foam cells in atherosclerotic lesions of Ldlr mice. C.pn-induced acceleration of atherosclerosis was significantly dependent on NLRP3 and caspase-1. We discovered that C.pn-induced extracellular IL-1β triggers a negative feedback loop to inhibit GPR109a and ABCA1 expression and cholesterol efflux, leading to accumulation of intracellular cholesterol and foam cell formation. Gpr109a and Abca1 were both upregulated in plaque lesions in Nlrp3 mice in both hyperlipidemic and C.pn infection models. Mature IL-1β and cholesterol may compete for access to the ABCA1 transporter to be exported from macrophages. C.pn exploits this metabolic-immune crosstalk, which can be modulated by NLRP3 inhibitors to alleviate atherosclerosis.
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http://dx.doi.org/10.1016/j.cmet.2018.05.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6125162PMC
September 2018

Optimal tube length of orotracheal intubation for mice.

Lab Anim 2019 Feb 13;53(1):79-83. Epub 2018 Apr 13.

Department of Pediatrics, Division of Infectious Diseases and Immunology, Cedars-Sinai Medical Center, Los Angeles, California, USA.

Endotracheal tube (ETT) management is an essential technique in handling mice with mechanical ventilators. Malposition into bronchi causes not only lethal complications for them but also less efficient mechanical ventilation. However, in general, it is difficult to know whether the ETT is placed with appropriate depth into the trachea of mice. We measured the distance from incisors to the bifurcation of trachea of multiple mice, and created a new estimation formula to obtain the suitable ETT length for mice with a body weight range from 17 g to 25 g: length (mm) = 0.5 × bodyweight (g) + 7. However, millimeter step adjustments are impracticable. Thus, slightly shorter than 2 cm (18-20 mm) may be the universal ETT length for mice with bodyweight > 17 g. Furthermore, their foot size may be a good alternative to predict the individual optimal ETT length for mice.
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http://dx.doi.org/10.1177/0023677218765032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6203655PMC
February 2019

Chlamydia and Lipids Engage a Common Signaling Pathway That Promotes Atherogenesis.

J Am Coll Cardiol 2018 04;71(14):1553-1570

Department of Pediatrics, Division of Pediatric Infectious Diseases and Immunology, Cedars-Sinai Medical Center, Los Angeles, California; Department of Biomedical Sciences, Infectious and Immunologic Diseases Research Center, Cedars-Sinai Medical Center, Los Angeles, California. Electronic address:

Background: Recent studies indicate that Toll-like receptor 4 (TLR4) and myeloid differentiation factor 88 (MyD88) signaling promote the development of high fat diet-induced atherosclerosis in hypercholesterolemic mice.

Objectives: The authors investigated the role of TLR4/MyD88 signaling in hematopoietic and stromal cells in the development and infection-mediated acceleration of atherosclerosis.

Methods: The authors generated bone marrow chimeras between wild-type and Tlr4 mice, as well as wild-type and Myd88 mice. All mice were on the Apoe background and fed high fat diet. The authors infected the chimeric mice with C. pneumoniae (CP) and fed them high fat diet.

Results: Aortic sinus plaques and lipid content were significantly reduced in Apoe mice that received Tlr4or Myd88 bone marrow compared with control animals despite similar cholesterol levels. Similarly, Tlr4 or Myd88 deficiency in stromal cells also led to a reduction in the lesion area and lipid in aortic sinus plaques. MyD88 expression only in CD11c+ dendritic cells (myeloid cells) in cells was sufficient in otherwise MyD88-deficient mice to induce CP infection-mediated acceleration of atherosclerosis, underlining the key role of MyD88 in CD11c+ dendritic cells (myeloid cells). Whereas CP infection markedly accelerated atherosclerosis in TLR4- or MyD88-positive chimeras, CP infection had a minimal effect on atherosclerosis in TLR4- or MyD88-deficient mice (either in the hematopoietic or stromal cell compartments).

Conclusions: The authors show that both CP infection and metabolic stress associated with dyslipidemia use the same innate immune response pathway, utilizing TLR4/MyD88 signaling, with similar relative contributions in bone marrow-derived hematopoietic cells and in stromal cells. Further studies are required to understand this intricate and complex cross talk among innate and adaptive immune systems in various conditions to more effectively design dendritic cell-mediated atheroprotective vaccines and other therapeutic strategies.
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http://dx.doi.org/10.1016/j.jacc.2018.01.072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6042865PMC
April 2018

Quercetin Inhibits Inflammasome Activation by Interfering with ASC Oligomerization and Prevents Interleukin-1 Mediated Mouse Vasculitis.

Sci Rep 2017 02 2;7:41539. Epub 2017 Feb 2.

Department of Pediatric, Infectious diseases and Immunology, Cedars-Sinai Medical Center, Los Angeles, California, USA.

Interleukin-1β (IL-1β) is a highly inflammatory cytokine that significantly contributes to both acute and chronic inflammatory diseases. The secretion of IL-1β requires a unique protease, caspase-1, which is activated by various protein platforms called inflammasomes. Data suggests a key role for mitochondrial reactive oxygen species for inflammasome activation. Flavonoids constitute a group of naturally occurring polyphenolic molecules with many biological activities, including antioxidant effects. In this study, we investigated the effect of three flavonoids, quercetin (QUC), naringenin, and silymarim on inflammasome activation. We found that QUC inhibits IL-1β secretion by both the NLRP3 and AIM2 inflammasome in a dose dependent manner, but not the NLRC4 inflammasome. QUC inhibition of the inflammasome was still observed in Atg16l1 knockout macrophages, indicating that QUC's effect was autophagy independent. Since QUC inhibited both NLRP3 and AIM2 inflammasomes but not NLRC4, we assessed ASC speck formation. QUC reduced ASC speck formation and ASC oligomerization compared with controls. Additionally, QUC inhibited IL-1β in Cryopyrin-Associated Periodic Syndromes (CAPS) macrophages, where NLRP3 inflammasome is constitutively activated. In conclusion, QUC inhibits both the NLRP3 and AIM2 inflammasome by preventing ASC oligomerization and may be a potential therapeutic candidate for Kawasaki disease vasculitis and other IL-1 mediated inflammatory diseases.
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http://dx.doi.org/10.1038/srep41539DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5288648PMC
February 2017

The microbiome in asthma.

Curr Opin Pediatr 2016 12;28(6):764-771

aDivision of Pediatric Infectious Diseases and Immunology, Infectious and Immunological Diseases Research Center, Department of Biomedical Sciences, Cedars-Sinai Medical Center bDavid Geffen School of Medicine at UCLA, Los Angeles, California, USA.

Purpose Of Review: Asthma is a complex and heterogeneous disease with strong genetic and environmental components that manifests within a variety of clinical features and diverse patterns of immune responses. Asthma prevalence has dramatically increased over the last decade in Westernized societies, thereby suggesting a key function of environmental factors in disease promotion and development.

Recent Findings: 'Early-life' microbial exposure and bacterial colonization are crucial for the maturation and the education of the immune system. The commensal flora is also critical in order to maintain immune homeostasis at the mucosal surfaces and may consequently play an important function in allergic disease development. Recent evidence demonstrates that asthma influences and is also impacted by the composition and function of the human intestinal and respiratory microbiome.

Summary: In this review, we summarize the most recent findings on how asthma development is connected with respiratory and intestinal microbial dysbiosis. We highlight and discuss recent research that reveals the existence of a 'gut-lung' microbial axis and its impact on asthma development. We also analyze how 'early-life' microbial exposure affects the immune response and the consequences for asthma development.
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http://dx.doi.org/10.1097/MOP.0000000000000419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5241015PMC
December 2016

CD8+ T Cells Contribute to the Development of Coronary Arteritis in the Lactobacillus casei Cell Wall Extract-Induced Murine Model of Kawasaki Disease.

Arthritis Rheumatol 2017 Feb;69(2):410-421

Cedars-Sinai Medical Center and University of California, Los Angeles.

Objective: Kawasaki disease (KD) is the leading cause of acquired heart disease among children in developed countries. Coronary lesions in KD in humans are characterized by an increased presence of infiltrating CD3+ T cells; however, the specific contributions of the different T cell subpopulations in coronary arteritis development remain unknown. Therefore, we sought to investigate the function of CD4+ and CD8+ T cells, Treg cells, and natural killer (NK) T cells in the pathogenesis of KD.

Methods: We addressed the function of T cell subsets in KD development by using a well-established murine model of Lactobacillus casei cell wall extract (LCWE)-induced KD vasculitis. We determined which T cell subsets were required for development of KD vasculitis by using several knockout murine strains and depleting monoclonal antibodies.

Results: LCWE-injected mice developed coronary lesions characterized by the presence of inflammatory cell infiltrates. Frequently, this chronic inflammation resulted in complete occlusion of the coronary arteries due to luminal myofibroblast proliferation (LMP) as well as the development of coronary arteritis and aortitis. We found that CD8+ T cells, but not CD4+ T cells, NK T cells, or Treg cells, were required for development of KD vasculitis.

Conclusion: The LCWE-induced murine model of KD vasculitis mimics many histologic features of the disease in humans, such as the presence of CD8+ T cells and LMP in coronary artery lesions as well as epicardial coronary arteritis. Moreover, CD8+ T cells functionally contribute to the development of KD vasculitis in this murine model. Therapeutic strategies targeting infiltrating CD8+ T cells might be useful in the management of KD in humans.
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http://dx.doi.org/10.1002/art.39939DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5274597PMC
February 2017

Ogg1-Dependent DNA Repair Regulates NLRP3 Inflammasome and Prevents Atherosclerosis.

Circ Res 2016 Sep 6;119(6):e76-90. Epub 2016 Jul 6.

From the Departments of Pediatrics, Biomedical Sciences, and Infectious and Immunologic Diseases Research Center (IIDRC) (G.T., K.S., J.D., T.R.C., W.Z., S.C.), Department of Pathology (D.L.), Cedars-Sinai Medical Center, Los Angeles, CA; Department of Medicine, Barbra Streisand Women's Heart Center, Heart Institute of Cedars-Sinai (R.A.G.), Cedars-Sinai Medical Center, Los Angeles, CA; and David Geffen School of Medicine, University of California, Los Angeles (M.A.).

Rationale: Activation of NLRP3 (nucleotide-binding domain and leucine-rich repeat pyrin domain containing 3) inflammasome-mediating interleukin (IL)-1β secretion has emerged as an important component of inflammatory processes in atherosclerosis. Mitochondrial DNA (mtDNA) damage is detrimental in atherosclerosis, and mitochondria are central regulators of the nucleotide-binding domain and leucine-rich repeat pyrin domain containing 3 inflammasome. Human atherosclerotic plaques express increased mtDNA damage. The major DNA glycosylase, 8-oxoguanine glycosylase (OGG1), is responsible for removing the most abundant form of oxidative DNA damage.

Objective: To test the role of OGG1 in the development of atherosclerosis in mouse.

Methods And Results: We observed that Ogg1 expression decreases over time in atherosclerotic lesion macrophages of low-density lipoprotein receptor (Ldlr) knockout mice fed a Western diet. Ogg1(-/-)Ldlr(-/-) mice fed a Western diet resulted in an increase in plaque size and lipid content. We found increased oxidized mtDNA, inflammasome activation, and apoptosis in atherosclerotic lesions and also higher serum IL-1β and IL-18 in Ogg1(-/-)Ldlr(-/-) mice than in Ldlr(-/-). Transplantation with Ogg1(-/-) bone marrow into Ldlr(-/-) mice led to larger atherosclerotic lesions and increased IL-1β production. However, transplantation of Ogg1(-/-)Nlrp3(-/-) bone marrow reversed the Ogg1(-/-) phenotype of increased plaque size. Ogg1(-/-) macrophages showed increased oxidized mtDNA and had greater amounts of cytosolic mtDNA and cytochrome c, increased apoptosis, and more IL-1β secretion. Finally, we found that proatherogenic miR-33 can directly inhibit human OGG1 expression and indirectly suppress both mouse and human OGG1 via AMP-activated protein kinase.

Conclusions: OGG1 plays a protective role in atherogenesis by preventing excessive inflammasome activation. Our study provides insight into a new target for therapeutic intervention based on a link between oxidative mtDNA damage, OGG1, and atherosclerosis via NLRP3 inflammasome.
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http://dx.doi.org/10.1161/CIRCRESAHA.116.308362DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5010464PMC
September 2016

Immunological Consequences of Intestinal Fungal Dysbiosis.

Cell Host Microbe 2016 Jun 26;19(6):865-73. Epub 2016 May 26.

F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, and the Division of Immunology, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. Electronic address:

Compared to bacteria, the role of fungi within the intestinal microbiota is poorly understood. In this study we investigated whether the presence of a "healthy" fungal community in the gut is important for modulating immune function. Prolonged oral treatment of mice with antifungal drugs resulted in increased disease severity in acute and chronic models of colitis, and also exacerbated the development of allergic airway disease. Microbiota profiling revealed restructuring of fungal and bacterial communities. Specifically, representation of Candida spp. was reduced, while Aspergillus, Wallemia, and Epicoccum spp. were increased. Oral supplementation with a mixture of three fungi found to expand during antifungal treatment (Aspergillus amstelodami, Epicoccum nigrum, and Wallemia sebi) was sufficient to recapitulate the exacerbating effects of antifungal drugs on allergic airway disease. Taken together, these results indicate that disruption of commensal fungal populations can influence local and peripheral immune responses and enhance relevant disease states.
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http://dx.doi.org/10.1016/j.chom.2016.05.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4900921PMC
June 2016

Role of Interleukin-1 Signaling in a Mouse Model of Kawasaki Disease-Associated Abdominal Aortic Aneurysm.

Arterioscler Thromb Vasc Biol 2016 05 3;36(5):886-97. Epub 2016 Mar 3.

From the Division of Infectious Diseases and Immunology, Department of Biomedical Sciences and Pediatrics (D.W., T.R.C., M.N.R., Y.L., S.C., K.S., M.A.), Infectious and Immunologic Diseases Research Center, Department of Biomedical Sciences (T.R.C., S.C., K.S., M.A.), Biomedical Imaging Research Institute, Department of Biomedical Sciences (S.W., D.L.), and Division of Cardiology, Oppenheimer Atherosclerosis Research Center Cedars-Sinai Heart Institute (P.K.S.), Cedars-Sinai Medical Center, Los Angeles, CA; Division of Mucosal Immunology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan (Y.K.); Regeneron Pharmaceuticals, Tarrytown, NY (W.F., Y.B.); Pediatric Rheumatology, Hospital for Special Surgery and Weill Medical College of Cornell University, New York, NY (T.L.); Department of Pathology, David Geffen School of Medicine at UCLA, Los Angeles, CA (M.C.F.); Departments of Pediatrics (H.M.H.) and Medicine (H.M.H.), University of California, San Diego, La Jolla; and Department of Pediatrics, Rady Children's Hospital, San Diego, CA (H.M.H.).

Objective: Kawasaki disease (KD) is the most common cause of acquired cardiac disease in US children. In addition to coronary artery abnormalities and aneurysms, it can be associated with systemic arterial aneurysms. We evaluated the development of systemic arterial dilatation and aneurysms, including abdominal aortic aneurysm (AAA) in the Lactobacillus casei cell-wall extract (LCWE)-induced KD vasculitis mouse model.

Methods And Results: We discovered that in addition to aortitis, coronary arteritis and myocarditis, the LCWE-induced KD mouse model is also associated with abdominal aorta dilatation and AAA, as well as renal and iliac artery aneurysms. AAA induced in KD mice was exclusively infrarenal, both fusiform and saccular, with intimal proliferation, myofibroblastic proliferation, break in the elastin layer, vascular smooth muscle cell loss, and inflammatory cell accumulation in the media and adventitia. Il1r(-/-), Il1a(-/-), and Il1b(-/-) mice were protected from KD associated AAA. Infiltrating CD11c(+) macrophages produced active caspase-1, and caspase-1 or NLRP3 deficiency inhibited AAA formation. Treatment with interleukin (IL)-1R antagonist (Anakinra), anti-IL-1α, or anti-IL-1β mAb blocked LCWE-induced AAA formation.

Conclusions: Similar to clinical KD, the LCWE-induced KD vasculitis mouse model can also be accompanied by AAA formation. Both IL-1α and IL-1β play a key role, and use of an IL-1R blocking agent that inhibits both pathways may be a promising therapeutic target not only for KD coronary arteritis, but also for the other systemic arterial aneurysms including AAA that maybe seen in severe cases of KD. The LCWE-induced vasculitis model may also represent an alternative model for AAA disease.
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http://dx.doi.org/10.1161/ATVBAHA.115.307072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4850105PMC
May 2016

Infection and Inflammatory Diseases.

For Immunopathol Dis Therap 2016 ;7(3-4):237-254

Division of Pediatric Infectious Diseases and Immunology, Burns and Allen Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048.

, an obligate intracellular bacterial pathogen, has long been investigated as a potential developmental or exacerbating factor in various pathologies. Its unique lifestyle and ability to disseminate throughout the host while persisting in relative safety from the immune response has placed this obligate intracellular pathogen in the crosshairs as a potentially mitigating factor in chronic inflammatory diseases. Many animal model and human correlative studies have been performed to confirm or deny a role for infection in these disorders. In some cases, antibiotic clinical trials were conducted to prove a link between bacterial infections and atherosclerosis. In this review, we detail the latest information regarding the potential role that infection may have in chronic inflammatory diseases.
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http://dx.doi.org/10.1615/ForumImmunDisTher.2017020161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6345537PMC
January 2016

IL-1 Signaling Is Critically Required in Stromal Cells in Kawasaki Disease Vasculitis Mouse Model: Role of Both IL-1α and IL-1β.

Arterioscler Thromb Vasc Biol 2015 Dec 29;35(12):2605-16. Epub 2015 Oct 29.

From the Division of Pediatric Infectious Diseases and Immunology, Department of Pediatric, Infectious and Immunologic Diseases Research Center, Cedars-Sinai Medical Center, Los Angeles, CA (Y.L., D.W., J.D., K.S., S.C., G.H., T.R.C., M.A.); Department of Rheumatology, Pediatric Rheumatology, Hospital for Special Surgery and Weill Medical College of Cornell University, New York, NY (T.J.A.L.); Department of Pathology, David Geffen School of Medicine at UCLA (M.C.F.); and Department of Pediatrics, Pediatric Rheumatology, University of California, San Diego, La Jolla (H.M.H.).

Objective: Kawasaki disease (KD) is the most common cause of acute vasculitis and acquired cardiac disease among US children. We have previously shown that both TLR2/MyD88 and interleukin (IL)-1β signaling are required for the Lactobacillus casei cell wall extract-induced KD vasculitis mouse model. The objectives of this study were to investigate the cellular origins of IL-1 production, the role of CD11c(+) dendritic cells and macrophages, and the relative contribution of hematopoietic and stromal cells for IL-1 responsive cells, as well the MyD88 signaling, in Lactobacillus casei cell wall extract-induced KD mouse model of vasculitis.

Approach And Results: Using mouse knockout models and antibody depletion, we found that both IL-1α and IL-1β were required for Lactobacillus casei cell wall extract-induced KD. Both dendritic cells and macrophages were necessary, and we found that MyD88 signaling was required in both hematopoietic and stromal cells. However, IL-1 response and signaling were critically required in nonendothelial stromal cells, but not in hematopoietic cells.

Conclusions: Our results suggest that IL-1α and IL-1β, as well as CD11c(+) dendritic cells and macrophages, are essential for the development of KD vasculitis and coronary arteritis in this mouse model. Bone marrow chimera experiments suggest that MyD88 signaling is important in both hematopoietic and stromal cells, whereas IL-1 signaling and response are required only in stromal cells, but not in endothelial cells. Determining the role of IL-1α and IL-1β and of specific cell types in the KD vasculitis mouse model may have important implications for the design of more targeted therapies and understanding of the molecular mechanisms of KD immunopathologies.
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http://dx.doi.org/10.1161/ATVBAHA.115.306475DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4662607PMC
December 2015

POPsicle for Fever! Cooling Down the Inflammasome.

Immunity 2015 Aug;43(2):213-5

Departments of Biomedical Sciences and Pediatrics, Divisions of Infectious Diseases and Immunology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Infectious and Immunologic Diseases Research Center, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. Electronic address:

Inhibition of the inflammasome might be beneficial for numerous inflammatory pathologies. In this issue of Immunity, de Almeida et al. (2015) report that the PYRIN domain-only protein (POP1) efficiently inhibits inflammasome activation, identifying it as a pan-inflammasome inhibitor.
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http://dx.doi.org/10.1016/j.immuni.2015.08.004DOI Listing
August 2015

Nicotinamide exacerbates hypoxemia in ventilator-induced lung injury independent of neutrophil infiltration.

PLoS One 2015 13;10(4):e0123460. Epub 2015 Apr 13.

Division of Pediatric Infectious Diseases and Immunology, Cedars-Sinai Medical Center, Los Angeles, CA, United States of America; Infectious and Immunologic Diseases Research Center, Cedars-Sinai Medical Center, Los Angeles, CA, United States of America.

Background: Ventilator-induced lung injury is a form of acute lung injury that develops in critically ill patients on mechanical ventilation and has a high degree of mortality. Nicotinamide phosphoribosyltransferase is an enzyme that is highly upregulated in ventilator-induced lung injury and exacerbates the injury when given exogenously. Nicotinamide (vitamin B3) directly inhibits downstream pathways activated by Nicotinamide phosphoribosyltransferase and is protective in other models of acute lung injury.

Methods: We administered nicotinamide i.p. to mice undergoing mechanical ventilation with high tidal volumes to study the effects of nicotinamide on ventilator-induced lung injury. Measures of injury included oxygen saturations and bronchoalveolar lavage neutrophil counts, protein, and cytokine levels. We also measured expression of nicotinamide phosophoribosyltransferase, and its downstream effectors Sirt1 and Cebpa, Cebpb, Cebpe. We assessed the effect of nicotinamide on the production of nitric oxide during ventilator-induced lung injury. We also studied the effects of ventilator-induced lung injury in mice deficient in C/EBPε.

Results: Nicotinamide treatment significantly inhibited neutrophil infiltration into the lungs during ventilator-induced lung injury, but did not affect protein leakage or cytokine production. Surprisingly, mice treated with nicotinamide developed significantly worse hypoxemia during mechanical ventilation. This effect was not linked to increases in nitric oxide production or alterations in expression of Nicotinamide phosphoribosyl transferase, Sirt1, or Cebpa and Cebpb. Cebpe mRNA levels were decreased with either nicotinamide treatment or mechanical ventilation, but mice lacking C/EBPε developed the same degree of hypoxemia and ventilator-induced lung injury as wild-type mice.

Conclusions: Nicotinamide treatment during VILI inhibits neutrophil infiltration of the lungs consistent with a strong anti-inflammatory effect, but paradoxically also leads to the development of significant hypoxemia. These findings suggest that pulmonary neutrophilia is not linked to hypoxemia in ventilator-induced lung injury, and that nicotinamide exacerbates hypoxemia during VILI.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0123460PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4395431PMC
January 2016

Lipopolysaccharide Induces Alveolar Macrophage Necrosis via CD14 and the P2X7 Receptor Leading to Interleukin-1α Release.

Immunity 2015 Apr 7;42(4):640-53. Epub 2015 Apr 7.

Departments of Biomedical Sciences, Medicine and Pediatrics, Divisions of Infectious Diseases and Immunology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Infectious and Immunologic Diseases Research Center, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; David Geffen School of Medicine, UCLA, Los Angeles, CA 90048, USA. Electronic address:

Acute lung injury (ALI) remains a serious health issue with little improvement in our understanding of the pathophysiology and therapeutic approaches. We investigated the mechanism that lipopolysaccharide (LPS) induces early neutrophil recruitment to lungs and increases pulmonary vascular permeability during ALI. Intratracheal LPS induced release of pro-interleukin-1α (IL-1α) from necrotic alveolar macrophages (AM), which activated endothelial cells (EC) to induce vascular leakage via loss of vascular endothelial (VE)-cadherin. LPS triggered the AM purinergic receptor P2X7(R) to induce Ca(2+) influx and ATP depletion, which led to necrosis. P2X7R deficiency significantly reduced necrotic death of AM and release of pro-IL-1α into the lung. CD14 was required for LPS binding to P2X7R, as CD14 neutralization significantly diminished LPS induced necrotic death of AM and pro-IL-1α release. These results demonstrate a key role for pro-IL-1α from necrotic alveolar macrophages in LPS-mediated ALI, as a critical initiator of increased vascular permeability and early neutrophil infiltration.
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http://dx.doi.org/10.1016/j.immuni.2015.03.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4423803PMC
April 2015

Mast cells play an important role in chlamydia pneumoniae lung infection by facilitating immune cell recruitment into the airway.

J Immunol 2015 Apr 9;194(8):3840-51. Epub 2015 Mar 9.

Division of Pediatric Infectious Diseases and Immunology, Department of Biomedical Sciences, Cedars-Sinai Medical Center and David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90048;

Mast cells are known as central players in allergy and anaphylaxis, and they play a pivotal role in host defense against certain pathogens. Chlamydia pneumoniae is an important human pathogen, but it is unclear what role mast cells play during C. pneumoniae infection. We infected C57BL/6 (wild-type [WT]) and mast cell-deficient mice (Kit(W-sh/W-sh) [Wsh]) with C. pneumoniae. Wsh mice showed improved survival compared with WT mice, with fewer cells in Wsh bronchoalveolar lavage fluid (BALF), despite similar levels of cytokines and chemokines. We also found a more rapid clearance of bacteria from the lungs of Wsh mice compared with WT mice. Cromolyn, a mast cell stabilizer, reduced BALF cells and bacterial burden similar to the levels seen in Wsh mice; conversely, Compound 48/80, a mast cell degranulator, increased the number of BALF cells and bacterial burden. Histology showed that WT lungs had diffuse inflammation, whereas Wsh mice had patchy accumulations of neutrophils and perivascular accumulations of lymphocytes. Infected Wsh mice had reduced amounts of matrix metalloprotease-9 in BALF and were resistant to epithelial integral membrane protein degradation, suggesting that barrier integrity remains intact in Wsh mice. Mast cell reconstitution in Wsh mice led to enhanced bacterial growth and normal epithelial integral membrane protein degradation, highlighting the specific role of mast cells in this model. These data suggest that mast cells play a detrimental role during C. pneumoniae infection by facilitating immune cell infiltration into the airspace and providing a more favorable replicative environment for C. pneumoniae.
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http://dx.doi.org/10.4049/jimmunol.1402685DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4390505PMC
April 2015

A single infection with Chlamydia pneumoniae is sufficient to exacerbate atherosclerosis in ApoE deficient mice.

Cell Immunol 2015 Mar 30;294(1):25-32. Epub 2015 Jan 30.

Division of Pediatric Infectious Diseases and Immunology, Cedars Sinai Medical Center and David Geffen School of Medicine, University of California, Los Angeles, CA 90048, USA. Electronic address:

Several studies have demonstrated a strong link between Chlamydia pneumoniae (Cp) infection and atherosclerosis progression/exacerbation. Here, we try to understand whether a single administration of Cp could exacerbate atherosclerosis. Apoe(-/-) mice were intranasally infected with Cp followed by a high fat diet. Mice were sacrificed at different time points after Cp infection to monitor the development of the atheroma. Cp infection increased lipid content in the aortic sinus of Apoe(-/-) mice starting from 8 weeks. This was associated with increased numbers of active myeloid dendritic cells and plasmacytoid DCs which were co-localized with T-cells in the atherosclerotic plaque. The serum levels of IFN-γ showed a Th1-like environment typical of atherosclerosis. In conclusion, we demonstrate that one dose of Cp could exacerbate atherosclerotic lesion development, triggering innate immune cell accumulation early on that allowed the involvement of Th1-like cells in the exacerbation of the atherosclerotic plaque at later time points.
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http://dx.doi.org/10.1016/j.cellimm.2015.01.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4391498PMC
March 2015

Alternatively spliced myeloid differentiation protein-2 inhibits TLR4-mediated lung inflammation.

J Immunol 2015 Feb 9;194(4):1686-94. Epub 2015 Jan 9.

Division of Infectious Diseases and Immunology, Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, CA 90048; Department of Biomedical Sciences, Infectious and Immunologic Diseases Research Center, Cedars-Sinai Medical Center, Los Angeles, CA 90048; and

We previously identified a novel alternatively spliced isoform of human myeloid differentiation protein-2 (MD-2s) that competitively inhibits binding of MD-2 to TLR4 in vitro. In this study, we investigated the protective role of MD-2s in LPS-induced acute lung injury by delivering intratracheally an adenovirus construct that expressed MD-2s (Ad-MD-2s). After adenovirus-mediated gene transfer, MD-2s was strongly expressed in lung epithelial cells and readily detected in bronchoalveolar lavage fluid. Compared to adenovirus serotype 5 containing an empty vector lacking a transgene control mice, Ad-MD-2s delivery resulted in significantly less LPS-induced inflammation in the lungs, including less protein leakage, cell recruitment, and expression of proinflammatory cytokines and chemokines, such as IL-6, keratinocyte chemoattractant, and MIP-2. Bronchoalveolar lavage fluid from Ad-MD-2s mice transferred into lungs of naive mice before intratracheal LPS challenge diminished proinflammatory cytokine levels. As house dust mite (HDM) sensitization is dependent on TLR4 and HDM Der p 2, a structural homolog of MD-2, we also investigated the effect of MD-2s on HDM-induced allergic airway inflammation. Ad-MD-2s given before HDM sensitization significantly inhibited subsequent allergic airway inflammation after HDM challenge, including reductions in eosinophils, goblet cell hyperplasia, and IL-5 levels. Our study indicates that the alternatively spliced short isoform of human MD-2 could be a potential therapeutic candidate to treat human diseases induced or exacerbated by TLR4 signaling, such as Gram-negative bacterial endotoxin-induced lung injury and HDM-triggered allergic lung inflammation.
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http://dx.doi.org/10.4049/jimmunol.1402123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4323992PMC
February 2015