Research Project
10084247
Macrophages play a key role in the pathogenesis of various autoimmune and rheumatic diseases. An important mechanism by which activated macrophages contribute to disease pathogenesis is production of inflammatory cytokines such as TNF, IL-1 and IL-6. These cytokines are canonical NF-?B target genes and validated therapeutic targets. The long term goals of this project are to understand how inflammatory macrophage activation is regulated, with the associated goal of developing new therapies that selectively suppress pathogenic macrophage functions, while preserving homeostatic functions and host defense. Type I IFNs and IFN-? are important regulators of immunity and inflammation. IFNs activate the JAK- STAT signaling pathway to induce canonical interferon-stimulated genes (ISGs). Expression of IFN target genes (termed an ?IFN signature?) is one of the most prominent molecular pathways activated in several autoimmune diseases including RA, lupus nephritis, and macrophage activation syndrome (MAS) (and related familial hemophagocytic lymphohistiocytosis (fHLH)). IFNs are clearly pathogenic in monogenic ?interferonopathies? and fHLH, where patients are responsive to JAK inhibitors and IFN-? blockade. JAK inhibitors, which target IFNs amongst other cytokines, are effective in RA and are being tested in SLE. Although IFNs do not directly activate pathogenic non-ISG inflammatory NF-?B target genes such as TNF, IL1B and IL6, they potentiate induction of these genes by TNF and TLRs. This supports the possibility that the therapeutic efficacy of IFN blockade or Jak inhibitors may be mediated at least in part by direct suppression of inflammatory cytokine production in macrophages. In accord with this notion, JAK inhibitors decrease inflammatory responses and cytokines in RA patients, primed human macrophages, RA synovial macrophages and tissue explants, and in preclinical models of arthritis and MAS/fHLH. In the previous project period we found that IFN-JAK-STAT signaling induces chromatin remodeling at inflammatory NF-?B target genes to make these genes hyper-responsive to inflammatory signals and resistant to suppression. IFNs also selectively suppressed components of the macrophage response to the suppressive cytokine IL-10 by deactivating enhancers. These data provide insights into pathways that connect IFN-JAK-STAT signaling to inflammatory NF-?B target genes and support our overarching hypothesis that IFNs help drive inflammatory non-ISG gene expression via chromatin-based mechanisms. In this project we will investigate epigenetic mechanisms by which IFNs drive macrophage activation and expression of pathogenic NF-?B target genes such as TNF, IL1B and IL6, and mechanisms by which JAK inhibitors suppress these genes. We anticipate that our studies will yield insights that can be used to develop novel therapeutic strategies to suppress inflammatory responses, and help understand how epigenetic mechanisms can contribute to poor efficacy of therapies that target upstream signaling pathways.
