PROJECT SUMMARY/ABSTRACT: Intestinal macrophage dysfunction is recognized as a central component to the pathogenesis of IBD. Intestinal macrophages (M?) exhibit an ?anergic?/anti-inflammatory phenotype in response to bacterial products and are critical in maintaining gut homeostasis. They are generated through continuous replenishment by circulating CCR2+Ly6Chi monocytes that differentiate locally into mature, anti-inflammatory macrophages. Intestinal macrophages are characterized by high expression of the chemokine receptor CX3CR1 and MHC class II molecules and produce high levels of IL-10 in response to LPS stimulation. Colonic macrophages are critical in the differentiation of Foxp3+ regulatory T cells. However, the molecular cues that drive the development of ?regulatory? intestinal macrophages are poorly characterized. We have recently demonstrated that the TGF? early response gene, KLF10, which belongs to a Sp1/Krüppel-like zinc finger transcription factor, is critically involved in regulating colitis development though colonic macrophage dysregulation. KLF10 may suppress macrophages activation at least in part through augmenting TGF? signaling. We have shown that, similarly to CD8+ T lymphocytes, KLF10 directly binds to the TGF?RII promoter in macrophages, leading to enhanced gene expression through histone H3 acetylation. Collectively, our data reveal a critical role for KLF10 in the epigenetic regulation of TGF?RII expression in macrophages and the acquisition of a regulatory phenotype that contributes to intestinal mucosal homeostasis. However, regulation of TGF?RII expression may not be the only mechanism by which KLF10 may regulate the generation of the anti-inflammatory intestinal macrophage phenotype. We have also shown that KLF10 may directly regulate primarily the expression of early inflammatory genes in macrophages such as CXCL1 and TNF-?, but has no effect on the regulation of other genes such as CCL2 or CCL3. We, thus, propose that KLF10 is an important transcriptional regulator of intestinal macrophage differentiation and anti-inflammatory function in vivo. KLF10 may epigenetically regulate the transition of inflammatory CCR2+Ly6Chi monocytes to tissue resident macrophages with potent anti- inflammatory properties (e.g. suppression of pro-inflammatory gene expression and up-regulation of IL-10). In the current proposal, we will further dissect the molecular pathways by which KLF10 regulates LPS-induced pro-inflammatory gene expression in intestinal and BM-derived macrophages. Our CENTRAL HYPOTHESIS is that KLF10 epigenetically regulates macrophage activation resulting in the development of anti-inflammatory intestinal macrophage which control mucosal inflammation in vivo. The specific aims of our proposal include: Aim #1: KLF10 epigenetically regulates the anti-inflammatory program of intestinal macrophages. Explore the epigenetic mechanisms by which KLF10 regulates pro-inflammatory gene expression in macrophages. Aim #2: KLF10 deficiency in Innate Immune Cells leads to mucosal immune dysregulation and colitis. Characterize the functional effect of KLF10 deficiency in Innate Immune Cells in the development of T cell- mediated colitis.
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