Resistin-like molecule α enhances myeloid cell activation and promotes colitis

Background

Resistin-like molecule (Relm) α is a secreted protein and a hallmark signature gene for alternatively activated macrophages. Relm-α is highly induced by allergic inflammatory triggers and perceived to promote tissue repair. Yet the function of Relm-α remains unknown.

Objective

We sough to determine the role of Relm-α in dextran sodium sulfate (DSS)–induced colonic injury.

Methods

The cellular source of Relm-α was determined after oral DSS-induced colitis. Retnla^−/− mice were generated, subjected to DSS treatment, and monitored for disease progression (clinical and histopathologic features). Cytokine production in the supernatants of ex vivo colon cultures, and of LPS-stimulated macrophages incubated with Relm-α was assessed. Relm-α was administered intraperitoneally, and the cellular recruitment to the peritoneum was assessed.

Results

After innate intestinal stimulation with DSS, Relm-α was highly expressed by eosinophils and epithelial cells. Retnla gene–targeted mice were protected from DSS-induced colitis (eg, decreased diarrhea, rectal bleeding, colon shortening, disease score, and histopathologic changes). Relm-α coactivated IL-6 and TNF-α release and inhibited IL-10 release from LPS-activated bone marrow–derived macrophages. Consistent with these finding, colon cultures of DSS-treated Retnla^−/− mice produced decreased IL-6 and increased IL-10 ex vivo. Furthermore, Retnla^−/− mice had substantially decreased c-Jun N-terminal kinase phosphorylation in vivo. In vivo administration of Relm-α initiated cellular recruitment to the peritoneum, and Relm-α was able to induce eosinophil chemotaxis in vitro.

Conclusions

These findings demonstrate a central proinflammatory role for Relm-α in colonic innate immune responses, identifying a novel pathway for regulation of macrophage activation.

Key words: Resistin-like molecule α, colitis, macrophages, eosinophils, LPS, inflammation, inflammatory bowel disease

Abbreviations used: DAPI, 4′,6-Diamidino-2-phenylindole dihydrochloride, DSS, Dextran sodium sulfate, IBD, Inflammatory bowel disease, MBP, Major basic protein, pJNK, Phospho–c-Jun N-terminal kinase, Relm, Resistin-like molecule