Abstract
A diverse spectrum of immune cells populates the intestinal mucosa reflecting the continuous stimulation by luminal antigens. In lesions of patients with inflammatory bowel disease, an aberrant inflammatory process is characterized by a very prominent infiltrate of activated immune cells producing cytokines and chemokines. These mediators perpetuate intestinal inflammation or may contribute to mucosal protection depending on the cellular context. In order to further characterize this complex immune cell network in intestinal inflammation, we investigated the contribution of the chemokine receptor CCR8 to development of colitis using a mouse model of experimental inflammation. We found that CCR8−/− mice compared to wildtype controls developed strong weight loss accompanied by increased histological and endoscopic signs of mucosal damage. Further experiments revealed that this gut protective function of CCR8 seems to be selectively mediated by the chemotactic ligand CCL1, which was particularly produced by intestinal macrophages during colitis. Moreover, we newly identified CCR8 expression on a subgroup of intestinal innate lymphoid cells producing IFN-γ and linked a functional CCL1/CCR8 axis with their abundance in the gut. Our data therefore suggest that this pathway supports tissue-specific ILC functions important for intestinal homeostasis. Modulation of this regulatory circuit may represent a new strategy to treat inflammatory bowel disease in humans.
Highlights
Inflammatory bowel diseases (IBD) are idiopathic inflammatory disorders of the gastrointestinal tract
CCR8 expression was upregulated in the intestinal mucosa of patients with ulcerative colitis and to a lesser extend Crohn’s disease compared to controls as evidenced by Quantitative PCR (qPCR) analysis of total RNA of gut tissue specimens (Figure 1A)
Mucosal CCR8 transcripts were increased in the context of dextrane sodium sulphate (DSS) induced colitis in mice (Figure 1B) indicating that this chemokine receptor might be somehow involved in the development of inflammatory bowel disease
Summary
Inflammatory bowel diseases (IBD) are idiopathic inflammatory disorders of the gastrointestinal tract. Nearly any cell type can produce chemokines upon stimulation, immune cells have been demonstrated to be a major source during inflammatory reactions Besides their manifest capacity to coordinate immune cell migration and positioning, various other regulatory roles during growth, survival, or cytokine production of immune cells have been revealed recently [7]. Recent data suggest a vital role of CCR8 for the local migration of CD301b+ dermal dendritic cells (DC) during cutaneous type 2 immune responses [15] In both humans and mice, CCR8 is expressed on Foxp3+ regulatory T cells and has been significantly implicated in their immunosuppressive functions in vivo [16,17,18]. We newly identified CCR8 expression on a subgroup of intestinal ILCs producing IFN-g and linked a functional CCL1/CCR8 axis with their abundance in the gut suggesting that this pathway axis supports tissue-specific ILC functions important for intestinal homeostasis
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