In systemic lupus erythematosus (SLE), CD4 T cells are critical drivers of the B cell- dependent autoantibody responses via provision of co-stimulatory signals and cytokines. Rapid removal of apoptotic cells (ACs) is considered central to the resolution of inflammation and in preventing autoimmune disease. Current dogma states that uptake of ACs by phagocytes induces synthesis of the immunoregulatory cytokine transforming growth factor- beta (TGF-b) through recognition of AC-specific molecules, resulting in the generation of an immunosuppressive state and prevention. Persistent self-antigens derived from ACs is a major causative event in the etiopathogenesis of SLE. Experimental studies have shown that dendritic cells (DCs) can process and present autoantigens from ACs in SLE. In contrast to the dogma, we observed that in the absence of microbial stimuli, human and mouse myeloid DCs and macrophages engulfing ACs produced substantial amounts of IL-23, IL-6, and TGF-b, the essential cytokines for the development of Th17 cells that have been strongly implicated in organ-specific pathogenesis of SLE. We further identified two novel transcription factors, LRRC16B and FLJ44967, as critically important and direct for the induction of IL-23 in phagocytes exposed to ACs. We hypothesize that in SLE-susceptible individuals/hosts, there is an overactivation of the IL-23/Th17-generating pathway in the process of clearance of ACs by phagocytes in a manner dependent on the expression and activities of LRRC16B and FLJ44967. We propose to: (1) Elucidate the cellular and molecular mechanisms whereby expression of LRRC16B and FLJ44967 is induced in professional phagocytes/APCs in response to ACs; (2) Investigate the role of LRRC16B and FLJ44967 in myeloid DCs engulfing ACs in Th17 development and SLE pathogenesis in the BWF1 model of lupus and non-autoimmune DWF1 mice. This investigation will lead to greater insights into the basis of Th17 development and activities in steady state physiology, and in the pathophysiology of autoimmune disorders.
This investigation pursues some critical questions based on a highly novel observation that several cytokines including IL-23 that are essential for the development of inflammatory and potentially autoreactive Th17 cells are induced during phagocytosis of apoptotic cells under steady state conditions. The study challenges the current dogma that phagocytosis of self- apoptotic cells results only in an immunosuppressive outcome. The outcome of this research will likely contribute to a conceptual advancement in this field, and to better understanding of the molecular mechanisms of the regulation of Th17 development and function in host defense and in autoimmunity, potentially providing the basis for highly innovative, targeted, and efficacious intervention in therapies for certain autoimmune disorders such as lupus, arthritis, and inflammatory bowel disease.
