Retnla (relmalpha/fizz1) suppresses helminth-induced Th2-type immunity.
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 rRelmalpha treatment. Studies with several cytokine knockout mice showed that expression of Retnla was dependent on IL-4 and IL-13 and inhibited by IFN-gamma, 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.
Pesce
John T
JT
Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
Ramalingam
Thirumalai R
TR
Wilson
Mark S
MS
Mentink-Kane
Margaret M
MM
Thompson
Robert W
RW
Cheever
Allen W
AW
Urban
Joseph F
JF
Wynn
Thomas A
TA
D000818:Animals; D004804:Eosinophils / Q000378:metabolism; D006099:Granuloma / Q000378:metabolism; D007113:Immunity, Innate; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology* / Q000627:therapeutic use; D007371:Interferon-gamma / Q000502:physiology; D018793:Interleukin-13 / Q000502:physiology; D015847:Interleukin-4 / Q000502:physiology; D008174:Lung Diseases, Parasitic / Q000188:drug therapy / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009559:Nippostrongylus / Q000276:immunology; D011658:Pulmonary Fibrosis / Q000469:parasitology; D012550:Schistosoma mansoni / Q000276:immunology; D012555:Schistosomiasis mansoni / Q000188:drug therapy / Q000276:immunology*; D017206:Strongylida Infections / Q000188:drug therapy / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology*
D036341:Intercellular Signaling Peptides and Proteins; D018793:Interleukin-13; C413576:Retnla protein, mouse; D015847:Interleukin-4; D007371:Interferon-gamma