Innate immune mechanisms underlying sterile inflammation and systemic sclerosis
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Systemic sclerosis (SSc) is a rare autoimmune disease characterized by peripheral vascular injury, fibrosis of the skin and other organs, and production of autoantibodies. Recent work by our group and others have suggested a role for innate immunity, perhaps activated by vascular injury, in driving the inflammation and fibrosis seen in the skin, lungs, and other tissues involved in this disease. The mechanisms driving the activation of innate immunity and the effects of this activation on SSc pathogenesis remain unclear. Toll-like receptors (TLRs) are an important family of receptors that drive innate immune responses after recognition of foreign or endogenous antigens. TLRs have been implicated in the pathogenesis of SSc and other autoimmune skin diseases. Using a muscle injury mouse model, we investigated the activation of TLRs after sterile injury. This study demonstrated that sterile muscle injury activated TLR3 signaling, which played an important role in cytokine responses and tissue repair. This study supported data from our group that showed that TLR3 activation might drive excess tissue repair in SSc skin. TLR9 has also been implicated in SSc pathogenesis. Therefore, we examined TLR9-mediated immune responses in the skin. Contrary to the fibrotic response of TLR3, chronic TLR9 activation induced severe inflammation characterized by the specific recruitment of inflammatory monocytes into the skin. We also determined that dermal macrophages were responsible for the strong cytokine and chemokine response, which may, collectively, recruit the monocytes. Macrophages and other immune cells are highly recruited to sites of perivascular inflammation in SSc skin. Thus, we assessed chemokine expression in SSc skin to determine their role in the pathogenesis. Chemokine expression analysis showed only a select group of chemokines upregulated, and suggested an important role specifically for CCL19 in immune cell recruitment and as a marker of perivascular inflammation. Overall, these studies demonstrate how various triggers of immune activation induce specific inflammatory or fibrotic immune responses, mainly driven by macrophages in the skin, providing new insight of how multifaceted activation of innate immunity could lead to the complex pathogenesis of SSc skin disease.
Thesis (Ph.D.)--Boston University