IL-17RA Signaling Reduces Inflammation and Mortality during Trypanosoma cruzi Infection by Recruiting Suppressive IL-10-Producing Neutrophils

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.

The IL17F and IL17RA Genetic Variants Increase Risk of Cerebral Malaria in Two African Populations

“…Both IL-17A and IL-17F stimulate matrix metalloproteases, thus increasing cell mobility. Studies in mice showed that IL-17A, IL-17E, IL-17F, and IL17RA are required for host resistance to Trypanosoma cruzi (29); furthermore, human resistance to kala azar caused by Leishmania donovani was associated with high levels of IL-17 and IL-22 responses (30). IL-17A and IL-17F are also crucial in the clearance of extracellular bacteria, such as Staphylococcus aureus, Citrobacter rodentium, and Klebsiella pneumoniae (31,32).…”

Interleukin-17 Protects against the Francisella tularensis Live Vaccine Strain but Not against a Virulent F. tularensis Type A Strain

“…Work by others showed that IL-17 was required for the induction of an IFN-␥ response in the lungs of mice infected with F. tularensis LVS (21), whereas in a parasite infection model, IL-17R␣ Ϫ/Ϫ mice were found to have an exaggerated IFN-␥ response (30). Therefore, to investigate the effect of impaired IL-17 signaling on the induction of IFN-␥ during infection with virulent F. tularensis, wild-type C57BL/6 or IL-17R␣ Ϫ/Ϫ mice were infected i.t.…”

Downregulation of Chicken Interleukin-17 Receptor A during Eimeria Infection

“…IL-17RA knockout mice have a reduced survival rate after Toxoplasma gondii infection (14) and Klebsiella pneumoniae inoculation (15,16). In contrast, IL-17RA-deficient mice have an increased survival rate after infections with Toxoplasma gondii (17) or Trypanosoma cruzi (18).…”