Crucial role of the melanocortin receptor MC1R in experimental colitis

Abstract

Background and aims: a-Melanocyte stimulating hormone (aMSH) is known to exert anti-inflammatory effects, for example in murine DSS (dextran sodium sulphate induced) colitis. The anti-inflammatory functions of aMSH are mediated by the melanocortin1-receptor (MC1R) in an autoregulatory loop. The aim of this study was therefore to determine whether a breakdown of the aMSH-MC1R pathway leads to worsening of disease. Methods: Experimental colitis was induced in mice with a frameshift mutation in the MC1R gene (MC1Re/ e), C57BL/6 wild type mice, and MC1Re/e-C57BL/6 bone marrow chimeras. The course of inflammation was monitored by weight loss, histological changes in the colon, and myeloperoxidase activity. In addition, MC1R expression was analysed in intestinal epithelial cells. Results: While the colon of untreated MC1Re/e appeared normal, the course of DSS-colitis in MC1Re/e mice was dramatically aggravated, with a significantly higher weight loss and marked histological changes compared to C57BL/6WT. The inflammation eventually led to death in all MC1Re/e, while all C57BL/6WT survived. Similar observations were detected in a transmissible murine colitis model induced by Citrobacter rodentium. Infected MC1Re/e showed delayed clearance of infection. To determine whether missing haematopoietic cell expressed MC1R was responsible, DSS colitis was induced in MC1Re/e-C57BL/6 bone marrow chimeras. MC1Re/e mice receiving MC1R+ bone marrow showed a similar course of inflammation to non-transplanted MC1Re/e. Likewise, transplantation of MC1R bone marrow into C57BL/6WT mice did not lead to any worsening of disease. Conclusions: This is the first study to show a functional role of MC1R in intestinal inflammation. The data suggest a pivotal role of non-haematopoietic cell expressed MC1R in the host's response to pathogenic stimuli.

Protectin D1 n-3 DPA and resolvin D5 n-3 DPA are effectors of intestinal protection

“…The clinical efficacy of anti-TNF therapy in IBD (3) supports this mechanism. Of interest, both PD1 n-3 DPA and RvD5 n-3 DPA did not regulate colonic levels of IL-10, setting these mediators apart from LXA 4 (28) or other proresolving mediators, like Annexin-A1 (29,30) and α-melanocyte stimulating hormone (31). To substantiate the physio-pathological impact of this new pathway, it was important to observe that inhibition of the enzyme responsible for conversion of DPA to DHA led to increased tissue levels of n-3 DPA-derived SPM, an effect linked to a reduction in systemic eicosanoid levels during I/R injury, supporting the host protective actions of these molecules.…”

Melanocortin-1 receptor activation is neuroprotective in mouse models of neuroinflammatory disease

“…8, A , Targeting melanocortin receptors to control peripheral inflammation has frequently been used. Accordingly, the administration of -MSH to mice or rats with psoriasis, colitis, rheumatoid arthritis, or infections resulted in a marked amelioration of disease mediated by the suppression of pathogenic effector cells, the down-regulation of pro-inflammatory and the induction of antiinflammatory cytokines (14,(39)(40)(41). Since some immunomodulatory properties of the melanocortin system, including the induction of functional Treg (14), might be relevant to CNS inflammation as well, we assessed the therapeutic potential of NDP-MSH, a melanocortin peptide recently approved for the treatment of certain skin diseases, during established inflammatory and degenerative CNS disorders.…”

Melanin-concentrating hormone as a mediator of intestinal inflammation

“…Thus, it is quite tempting to speculate that MCH might have similar effects on leptin expression in colonic epithelial cells (45) during inflammation. In further support of the proinflammatory effects of MCH in the intestine, ␣-MSH, a functional antagonist of MCH (48), reduces the clinical and histological severity of experimental colitis in rats (49), and a mutation in one of the ␣-MSH receptors aggravates colitis in mice (50).…”