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OX40L blockade protects against inflammation-driven fibrosis.

ABSTRACT: Treatment for fibrosis represents a critical unmet need, because fibrosis is the leading cause of death in industrialized countries, and there is no effective therapy to counteract the fibrotic process. The development of fibrosis relates to the interplay between vessel injury, immune cell activation, and fibroblast stimulation, which can occur in various tissues. Immunotherapies have provided a breakthrough in the treatment of immune diseases. The glycoprotein OX40-OX40 ligand (OX40L) axis offers the advantage of a targeted approach to costimulatory signals with limited impact on the whole immune response. Using systemic sclerosis (SSc) as a prototypic disease, we report compelling evidence that blockade of OX40L is a promising strategy for the treatment of inflammation-driven fibrosis. OX40L is overexpressed in the fibrotic skin and serum of patients with SSc, particularly in patients with diffuse cutaneous forms. Soluble OX40L was identified as a promising serum biomarker to predict the worsening of lung and skin fibrosis, highlighting the role of this pathway in fibrosis. In vivo, OX40L blockade prevents inflammation-driven skin, lung, and vessel fibrosis and induces the regression of established dermal fibrosis in different complementary mouse models. OX40L exerts potent profibrotic effects by promoting the infiltration of inflammatory cells into lesional tissues and therefore the release of proinflammatory mediators, thereafter leading to fibroblast activation.

SUBMITTER: Elhai M

PROVIDER: S-EPMC4941508 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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OX40L blockade protects against inflammation-driven fibrosis.

Elhai Muriel M Avouac Jérôme J Hoffmann-Vold Anna Maria AM Ruzehaji Nadira N Amiar Olivia O Ruiz Barbara B Brahiti Hassina H Ponsoye Matthieu M Fréchet Maxime M Burgevin Anne A Pezet Sonia S Sadoine Jérémy J Guilbert Thomas T Nicco Carole C Akiba Hisaya H Heissmeyer Vigo V Subramaniam Arun A Resnick Robert R Molberg Øyvind Ø Kahan André A Chiocchia Gilles G Allanore Yannick Y

Proceedings of the National Academy of Sciences of the United States of America 20160613 27

Treatment for fibrosis represents a critical unmet need, because fibrosis is the leading cause of death in industrialized countries, and there is no effective therapy to counteract the fibrotic process. The development of fibrosis relates to the interplay between vessel injury, immune cell activation, and fibroblast stimulation, which can occur in various tissues. Immunotherapies have provided a breakthrough in the treatment of immune diseases. The glycoprotein OX40-OX40 ligand (OX40L) axis offe ...[more]

PMID: 27298374

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Project description:AimsTransient Receptor Potential Melastatin 7 (TRPM7) cation channel is a chanzyme (channel + kinase) that influences cellular Mg2+ homeostasis and vascular signalling. However, the pathophysiological significance of TRPM7 in the cardiovascular system is unclear. The aim of this study was to investigate the role of this chanzyme in the cardiovascular system focusing on inflammation and fibrosis.Methods and resultsTRPM7-deficient mice with deletion of the kinase domain (TRPM7+/?kinase) were studied and molecular mechanisms investigated in TRPM7+/?kinase bone marrow-derived macrophages (BMDM) and co-culture systems with cardiac fibroblasts. TRPM7-deficient mice had significant cardiac hypertrophy, fibrosis, and inflammation. Cardiac collagen and fibronectin content, expression of pro-inflammatory mediators (SMAD3, TGF?) and cytokines [interleukin (IL)-6, IL-10, IL-12, tumour necrosis factor-?] and phosphorylation of the pro-inflammatory signalling molecule Stat1, were increased in TRPM7+/?kinase mice. These processes were associated with infiltration of inflammatory cells (F4/80+CD206+ cardiac macrophages) and increased galectin-3 expression. Cardiac [Mg2+]i, but not [Ca2+]i, was reduced in TRPM7+/?kinase mice. Calpain, a downstream TRPM7 target, was upregulated (increased expression and activation) in TRPM7+/?kinase hearts. Vascular functional and inflammatory responses, assessed in vivo by intra-vital microscopy, demonstrated impaired neutrophil rolling, increased neutrophil: endothelial attachment and transmigration of leucocytes in TRPM7+/?kinase mice. TRPM7+/?kinase BMDMs had increased levels of galectin-3, IL-10, and IL-6. In co-culture systems, TRPM7+/?kinase macrophages increased expression of fibronectin, proliferating cell nuclear antigen, and TGF? in cardiac fibroblasts from wild-type mice, effects ameliorated by MgCl2 treatment.ConclusionsWe identify a novel anti-inflammatory and anti-fibrotic role for TRPM7 and suggest that its protective effects are mediated, in part, through Mg2+-sensitive processes.

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OX40L blockade protects against inflammation-driven fibrosis.

Publications

OX40L blockade protects against inflammation-driven fibrosis.

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