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.
Highlights
Th1 and Th17 cytokines are believed to be proinflammatory, while Th2 cytokines were historically described as regulatory mediators [1,2]
Retnla is a member of a family of cysteine-rich secreted proteins, referred to as ‘resistin-like molecules’ or ‘found in inflammatory zone’ originally identified in the lung [15]
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
Summary
Th1 and Th17 cytokines are believed to be proinflammatory, while Th2 cytokines were historically described as regulatory mediators [1,2]. It is well established that Th2 responses, characterized by the production of IL-4, IL-5, and IL13, exhibit pleiotropic activities in host immunity [3]. In addition to their regulatory activities, they function as mediators of allergic inflammation, tissue remodeling, and fibrosis [4]. They regulate immune homeostasis in the gut and promote resistance to GI nematodes [5,6]. Among the list of unique Th2-inducible genes uncovered in these studies was Retnla (FIZZ1/Relma), which is induced to very high levels in a variety of tissues during Th2-polarized inflammatory responses [13,14]
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