Abstract
Stromal cells are emerging as key drivers of autoimmunity, partially because they produce inflammatory chemokines that orchestrate inflammation. Chemokine expression is regulated transcriptionally but also through posttranscriptional mechanisms, the specific drivers of which are still incompletely defined. CCL2 (MCP1) is a multifunctional chemokine that drives myeloid cell recruitment. During experimental autoimmune encephalomyelitis (EAE), an IL-17–driven model of multiple sclerosis, CCL2 produced by lymph node (LN) stromal cells was essential for immunopathology. Here, we showed that Ccl2 mRNA upregulation in human stromal fibroblasts in response to IL-17 required the RNA-binding protein IGF-2 mRNA-binding protein 2 (IGF2BP2, IMP2), which is expressed almost exclusively in nonhematopoietic cells. IMP2 binds directly to CCL2 mRNA, markedly extending its transcript half-life, and is thus required for efficient CCL2 secretion. Consistent with this, Imp2−/− mice showed reduced CCL2 production in LNs during EAE, causing impairments in monocyte recruitment and Th17 cell polarization. Imp2–/– mice were fully protected from CNS inflammation. Moreover, deletion of IMP2 after EAE onset was sufficient to mitigate disease severity. These data showed that posttranscriptional control of Ccl2 in stromal cells by IMP2 was required to permit IL-17–driven progression of EAE pathogenesis.
Highlights
Autoimmune diseases encompass a spectrum of disorders characterized by aberrant immunes response to self-antigens, usually of unknown etiology
We show that amplification of Ccl2 is mediated by IL-17 in mesenchymal cells from both mouse as well as human lymph node (LN) stroma
Induction of inflammatory genes is viewed in the context of promoter regulation, but many immune genes including Ccl2 are expressed at baseline tonic levels, and their capacity to be induced during immune insult is due to expanded transcript half-life or other post-transcriptional mechanisms [34]
Summary
Autoimmune diseases encompass a spectrum of disorders characterized by aberrant immunes response to self-antigens, usually of unknown etiology. Despite substantial advances in anticytokine biologic drugs, there is a major unmet need for more effective treatments for autoimmune conditions. Achieving this goal will require a better understanding of the molecular pathways and mechanisms that promote autoimmunity. Experimental autoimmune encephalomyelitis (EAE) is a widely used mouse model that has shaped our understanding of the pathogenesis of MS and many other autoimmune conditions. This model has been the impetus for effective therapeutic approaches for MS, the discovery of the Th17 pathway and inhibitors thereof [1]. During EAE, the generation of encephalitogenic Th17 cells is dependent on myelin antigen processing and presentation
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