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

Abstract

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.

Alternatively activated dendritic cells regulate CD4+T-cell polarization in vitro and in vivo

“…We show that treatment of DCs with IL-4 in vitro resulted in robust expression of a wide range of alternative activation markers at both the transcript and protein level, with a more selective expression of alternative activation markers RELMα and Ym1 in vivo. We further demonstrate a key role for DC-derived RELMα in promotion of optimal Th2 responses that contrasts with the previously suggested regulatory function of this alternative activation product (20)(21)(22). Together, these data reveal that the ability to respond to IL-4 is critical for optimal Th1 or Th2 priming by DCs through modulation of IL-12/IL-10 or RELMα production, respectively.…”

“…The phenotypes of aaMΦ populations, isolated from a variety of tissues in Th2 inflammatory settings, have been well characterized, with one hallmark being the abundant expression of markers RELMα and Ym1 (6). RELMα has also previously been identified in cells other than aaMΦs, including eosinophils and epithelial cells (10,20,22). To investigate whether DCs respond to Th2 environments in a manner similar to MΦs, mice were injected i.p.…”

The adipokine Retnla modulates cholesterol homeostasis in hyperlipidemic mice

“…Given that Retnla is an alternatively activated macrophage-inducible gene 15,16 that modulates immune responses in inflammatory diseases 13,18,36,37 , and that atherosclerosis can be considered both a lipid metabolism disorder and a chronic inflammatory disease 23 , we examined whether Retnla deficiency also influences inflammatory plaque phenotypes. Consistent with the increased en face plaque area, aortic root lesions were also increased in Ldlr À / À Retnla À / À mice compared with Ldlr À / À mice (Fig.…”

“…Faecal bile acid excretion (μmol per day per 100 g body weight) ARTICLE family members, Retnlb and resistin are implicated as mediators of inflammation 46,56,57 and abundantly expressed in macrophages of atheroma involved in atherosclerosis development 45,58 13,18 , while in a model of chronic inflammation by Schistosoma mansoni infection, both the lung inflammation and liver fibrosis were increased by Retnla deficiency via an enhanced Th2 immune responses 36,37 . These results suggest that the beneficial and detrimental roles of Retnla in inflammatory diseases are likely influenced by the type of immune stimulus, the duration of the stimulus exposure and the tissue type.…”

“…Retnla, adipokine, was initially found in allergic lung inflammation 10 . Its expression has been reported in lung, spleen, heart and mammary glands, as well as in white adipose tissue (WAT) [10][11][12] , and is highly inducible in epithelial cells, macrophages and eosinophils after inflammatory stimulations associated with parasites infection, allergy and tissue injury 10,13,14 . Exposure to the T helper (Th)2 cytokines IL-4 and IL-13 or environments involved in Th2 immune responses increased the expression of Retnla, identifying Retnla as a hallmark signature gene for alternatively activated macrophages [14][15][16] .…”