Retnla (Relmα/Fizz1) Suppresses Helminth-Induced Th2-Type Immunity

Abstract

Retnla (Resistin-like molecule alpha/FIZZ1) is induced during Th2 cytokine immune responses. However, the role of Retnla in Th2-type immunity is unknown. Here, using Retnla^−/− mice and three distinct helminth models, we show that Retnla functions as a negative regulator of Th2 responses. Pulmonary granuloma formation induced by the eggs of the helminth parasite Schistosoma mansoni is dependent on IL-4 and IL-13 and associated with marked increases in Retnla expression. We found that both primary and secondary pulmonary granuloma formation were exacerbated in the absence of Retlna. The number of granuloma-associated eosinophils and serum IgE titers were also enhanced. Moreover, when chronically infected with S. mansoni cercariae, Retnla^−/− mice displayed significant increases in granulomatous inflammation in the liver and the development of fibrosis and progression to hepatosplenic disease was markedly augmented. Finally, Retnla^−/− mice infected with the gastrointestinal (GI) parasite Nippostrongylus brasiliensis had intensified lung pathology to migrating larvae, reduced fecundity, and accelerated expulsion of adult worms from the intestine, suggesting Th2 immunity was enhanced. When their immune responses were compared, helminth infected Retnla^−/− mice developed stronger Th2 responses, which could be reversed by exogenous rRelmα treatment. Studies with several cytokine knockout mice showed that expression of Retnla was dependent on IL-4 and IL-13 and inhibited by IFN-γ, while tissue localization and cell isolation experiments indicated that eosinophils and epithelial cells were the primary producers of Retnla in the liver and lung, respectively. Thus, the Th2-inducible gene Retnla suppresses resistance to GI nematode infection, pulmonary granulomatous inflammation, and fibrosis by negatively regulating Th2-dependent responses. Retnla is a member of a family of cysteine-rich secreted proteins, referred to as ‘resistin-like molecules’ or ‘found in inflammatory zone’ that increase in expression during allergic reactions and following infection with a variety of metazoan parasites. Retnla was originally hypothesized to function as an effector molecule during helminth-induced Th2-type immune responses. Studies conducted here with Retnla-deficient mice, however, suggest that Retnla primarily functions as a regulatory molecule during helminth infection. Using three helminth model systems affecting three different organ systems, we show that Retlna is induced by IL-4 and IL-13 as a mechanism to suppress Th2-type immunity. Retnla deficiency increased inflammation in the lung following i.v. challenge with Schistosoma mansoni eggs. Retnla deficiency also accelerated the development of liver fibrosis following S. mansoni infection. This finding was particularly surprising since Retnla was previously shown to activate collagen-producing fibroblasts that induce fibrosis. Thus, Retnla may represent a novel target for the treatment of fibrotic diseases. Finally, resistance to the intestinal nematode parasite Nippostrongylus brasiliensis was significantly increased in the absence of Retnla. When viewed together, the combined results from all three models establish a critical role for the Th2-inducible gene Retnla (Fizz1/Relm-alpha) in the suppression of helminth-induced Th2-type immunity.