IL-17RA signaling reduces inflammation and mortality during trypanosoma cruzi infection by recruiting suppressive IL-10-producing neutrophils

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. © 2012 tosello boari et al.