Activation of Macrophages in Human Autoimmune Diseases

Activated macrophages play a key role in the pathogenesis of autoimmune diseases including rheumatoid arthritis (RA). Macrophages drive disease pathology largely through the production of inflammatory mediators and cytokines such as TNF, IL-1 and IL-6; these cytokines are validated therapeutic targets. The long term goals of this project are to understand mechanisms that regulate inflammatory cytokine production by macrophages and the role of these mechanisms in autoimmune arthritis pathogenesis. The importance of innate immune `priming' or `training' that amplifies induction of inflammatory NF- B target genes such as TNF, IL6 and IL1B by epigenetic mechanisms is being increasingly appreciated. Trained innate immunity confers protection after infections and vaccinations, and has recently been implicated in pathogenesis of inflammatory arthritis and other autoimmune diseases. The major macrophage-activating cytokine IFN- has long been appreciated to `prime' monocytes and macrophages (MonoMacs) for enhanced activation of NF-B target genes in response to inflammatory factors. Our lab has made key contributions to demonstrating that one mechanism of IFN--mediated priming is chromatin remodeling and training at inflammatory NF-B target gene loci. The importance of IFN- in innate immune priming and training has been shown in various in vivo systems. Recent high dimensional genomic studies, in which we participated, have highlighted a pervasive IFN signature in RA synovium, which is associated with NF-B target gene expression in pathogenic subsets of MonoMacs. This highlights the important question of the role of IFN- and its priming of pathogenic NF-B target genes in RA pathogenesis. In this project we will focus on regulation of MonoMac cytokine production in the context of RA synovitis, where MonoMacs are tightly linked to pathogenesis and we have decades of experience. In the previous project period we investigated mechanisms by which Jak-STAT signaling calibrates or `tunes' the NF-B gene response in primary human monocytes and implicated IRF and CEBP family transcription factors and associated chromatin remodeling and de novo enhancer formation in priming. We also characterized a mouse arthritis model that recapitulates pathogenic RA MonoMac subsets, exhibits co- activation of IFN- and NF-B pathways, and is augmented by training and immune checkpoint blockade. Our overarching hypothesis is that IFN--induced IRFs/CEBPs regulate recruitment of NF-B and chromatin remodeling enzymes to boost inflammatory gene responses, and these epigenetic mechanisms are important in arthritis pathogenesis. We will investigate mechanisms by which IFN- primes/trains MonoMacs for enhanced inflammatory gene expression, and the role of these mechanisms in inflammatory and autoimmune arthritis models. We anticipate our studies will yield insights that can be used to develop more effective and targeted therapeutic strategies for rheumatoid arthritis.