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

• Published in: Journal of allergy and clinical immunology 2008-12, Vol.122 (6), p.1200-1207.e1
• Main Authors: Munitz, Ariel, PhD, Waddell, Amanda, BSc, Seidu, Luqman, MD, Cole, Eric T., MSc, Ahrens, Richard, BSc, Hogan, Simon P., PhD, Rothenberg, Marc E., MD, PhD
• Format: Article
• Language: English
• Subjects: Allergy and Immunology; Animals; Biological and medical sciences; Bone Marrow Cells - metabolism; Bone Marrow Cells - pathology; Chemotaxis - drug effects; Chemotaxis - genetics; colitis; Colitis - chemically induced; Colitis - genetics; Colitis - metabolism; Colitis - pathology; Colon - metabolism; Colon - pathology; Cytokines - biosynthesis; Dextran Sulfate - toxicity; eosinophils; Eosinophils - metabolism; Eosinophils - pathology; Female; Fundamental and applied biological sciences. Psychology; Fundamental immunology; inflammation; inflammatory bowel disease; Intercellular Signaling Peptides and Proteins - genetics; Intercellular Signaling Peptides and Proteins - metabolism; JNK Mitogen-Activated Protein Kinases - metabolism; Lipopolysaccharides - pharmacology; LPS; Macrophage Activation - drug effects; Macrophage Activation - genetics; macrophages; Macrophages - metabolism; Macrophages - pathology; Male; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Knockout; Organ Culture Techniques; Peritoneum - metabolism; Peritoneum - pathology; Phosphorylation - drug effects; Rapid Publication; Resistin-like molecule α; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2008.10.017

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.