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Alternatively activated macrophage-derived RELM- is a negative regulator of type 2 inflammation in the lung

¹ Department of Pathobiology and ² Division of Gastroenterology, Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104
³ Regeneron Pharmaceuticals, Inc., Tarrytown, NY 10591
⁴ Amgen, Thousand Oaks, CA 91320

CORRESPONDENCE David Artis: dartis{at}vet.upenn.edu

Differentiation and recruitment of alternatively activated macrophages (AAMacs) are hallmarks of several inflammatory conditions associated with infection, allergy, diabetes, and cancer. AAMacs are defined by the expression of Arginase 1, chitinase-like molecules, and resistin-like molecule (RELM) /FIZZ1; however, the influence of these molecules on the development, progression, or resolution of inflammatory diseases is unknown. We describe the generation of RELM-–deficient (Retnla^–/–) mice and use a model of T helper type 2 (Th2) cytokine-dependent lung inflammation to identify an immunoregulatory role for RELM-. After challenge with Schistosoma mansoni (Sm) eggs, Retnla^–/– mice developed exacerbated lung inflammation compared with their wild-type counterparts, characterized by excessive pulmonary vascularization, increased size of egg-induced granulomas, and elevated fibrosis. Associated with increased disease severity, Sm egg–challenged Retnla^–/– mice exhibited elevated expression of pathogen-specific CD4⁺ T cell–derived Th2 cytokines. Consistent with immunoregulatory properties, recombinant RELM- could bind to macrophages and effector CD4⁺ Th2 cells and inhibited Th2 cytokine production in a Bruton's tyrosine kinase–dependent manner. Additionally, Retnla^–/– AAMacs promoted exaggerated antigen-specific Th2 cell differentiation. Collectively, these data identify a previously unrecognized role for AAMac-derived RELM- in limiting the pathogenesis of Th2 cytokine-mediated pulmonary inflammation, in part through the regulation of CD4⁺ T cell responses.

Abbreviations used: AAMac, alternatively activated macrophage; BAL, bronchoalveolar lavage; BMMac, BM-derived macrophage; BTK, Bruton's tyrosine kinase; DN, double negative; eGFP, enhanced GFP; IF, immunofluorescent; mRNA, messenger RNA; PEC, peritoneal cavity; RELM, resistin-like molecule; Sm, Schistosoma mansoni.

© 2009 Nair et al.
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