IL-17RA Signaling Reduces Inflammation and Mortality during Trypanosoma cruzi Infection by Recruiting Suppressive IL-10-Producing Neutrophils
Open Access
- 26 April 2012
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLoS Pathogens
- Vol. 8 (4), e1002658
- https://doi.org/10.1371/journal.ppat.1002658
Abstract
Members of the IL-17 cytokine family play an important role in protection against pathogens through the induction of different effector mechanisms. We determined that IL-17A, IL-17E and IL-17F are produced during the acute phase of T. cruzi infection. Using IL-17RA knockout (KO) mice, we demonstrate that IL-17RA, the common receptor subunit for many IL-17 family members, is required for host resistance during T. cruzi infection. Furthermore, infected IL-17RA KO mice that lack of response to several IL-17 cytokines showed amplified inflammatory responses with exuberant IFN-γ and TNF production that promoted hepatic damage and mortality. Absence of IL-17RA during T. cruzi infection resulted in reduced CXCL1 and CXCL2 expression in spleen and liver and limited neutrophil recruitment. T. cruzi-stimulated neutrophils secreted IL-10 and showed an IL-10-dependent suppressive phenotype in vitro inhibiting T-cell proliferation and IFN-γ production. Specific depletion of Ly-6G+ neutrophils in vivo during T. cruzi infection raised parasitemia and serum IFN-γ concentration and resulted in increased liver pathology in WT mice and overwhelming wasting disease in IL-17RA KO mice. Adoptively transferred neutrophils were unable to migrate to tissues and to restore resistant phenotype in infected IL-17RA KO mice but migrated to spleen and liver of infected WT mice and downregulated IFN-γ production and increased survival in an IL-10 dependent manner. Our results underscore the role of IL-17RA in the modulation of IFN-γ-mediated inflammatory responses during infections and uncover a previously unrecognized regulatory mechanism that involves the IL-17RA-mediated recruitment of suppressive IL-10-producing neutrophils. IL-17 family is comprised for six members (IL-17A to F) that have been reported to play protective effects in bacterial and fungal infections and contradictory roles in parasite infections. Using mice deficient in IL-17RA, the common receptor subunit for many IL-17 family members, we determined that these cytokines are required for host protection against the parasite Trypanosoma cruzi. In absence of IL-17 signaling, mice developed an aggravated infection with similar levels of parasite in blood but increased inflammation and tissue damage of vital organs such as liver. We evaluated the mechanisms underlying this increased susceptibility and determined that the absence of IL-17RA caused a reduced arrival of neutrophils to organs such as spleen and liver. Neutrophils are phagocytic cells with abilities to directly destroy pathogens and also to regulate the inflammatory response. Indeed, we determined that neutrophils from T. cruzi infected mice are poisoned to secrete the regulatory cytokine IL-10. Finally, by experiments of depletion and adoptive transfer of neutrophils we determined that, during T. cruzi infection, IL-17RA is required for the recruitment of neutrophils that destroy the parasite and that also regulate inflammatory responses and collateral tissue damage by secreting IL-10.Keywords
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