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Intestinal inflammation breaks established immune tolerance to a skin commensal


The gut and skin are major barrier tissues that house microbial communities capable of influencing host immunity. Under homeostatic conditions, resident microbes at each of these two sites are thought to have a dominant impact on local immune cell function. However, the prevalence of neutrophilic skin disorders among patients with Inflammatory Bowel Disease suggests that this compartmentalized control may not hold under disease conditions. We hypothesized that an altered immune response to gut-resident microbes during colitis may facilitate excessive inflammation directed at skin commensals. Using an established model, wherein neonatal colonization by Staphylococcus epidermidis facilitates development of adaptive immune tolerance and enrichment in S. epidermidis-specific CD4+ regulatory T cells (Tregs), we asked whether this tolerance to skin bacteria can be perturbed in the context of gut inflammation. Induction during adulthood of either chemically or genetically-mediated colitis, but not systemic inflammation alone, led to reduced percentages of S. epi-specific Tregs in skin and skin-draining lymph nodes (LN) and an increase in skin neutrophils. Intestinal presence of S. epidermidis and reduced percentages of S. epidermidis-specific Tregs at this site during colitis suggested initiation of this altered response in the gut. Consistent with this, adoptive transfer and photoconversion experiments revealed a colitis-induced increase in CD4+ T cell trafficking from gut-draining LN to skin-draining LN. Recovery in the percentage of S. epidermidis-specific Tregs in colitic Cd4creIl1r1fl/fl mice further indicated a role for circulating IL-1 cytokines in shifting the CD4+ skin commensal response during colitis. Collectively, these results identify a context in which there is breakdown in homeostatic separation of skin and gut host-microbe interactions and provide mechanistic insight into observed connections between inflammatory skin and intestinal diseases.

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