The IL-21 receptor augments Th2 effector function and alternative macrophage activation

Authors:
  • MKMallika Kaviratne
    Mallika Kaviratne
  • TRThirumalai R. Ramalingam
    Thirumalai R. Ramalingam
  • RTRobert W. Thompson
    Robert W. Thompson
  • ACAllen W. Cheever
    Allen W. Cheever
  • DYDeborah A. Young
    Deborah A. Young
  • MCMary Collins
    Mary Collins
  • MGMichael J. Grusby
    Michael J. Grusby
Open Access
Publisher website
Google Scholar
Abstract
The IL-21 receptor (IL-21R) shows significant homology with the IL-4R, and CD4+ Th2 cells are an important source of IL-21. Here we examined whether the IL-21R regulates the development of Th2 responses in vivo. To do this, we infected IL-21R–/– mice with the Th2-inducing pathogens Schistosoma mansoni and Nippostrongylus brasiliensis and examined the influence of IL-21R deficiency on the development of Th2-dependent pathology. We showed that granulomatous inflammation and liver fibrosis were significantly reduced in S. mansoni–infected IL-21R–/– mice and in IL-21R+/+ mice treated with soluble IL-21R–Fc (sIL-21R–Fc). The impaired granulomatous response was also associated with a marked reduction in Th2 cytokine expression and function, as evidenced by the attenuated IL-4, IL-13, AMCase, Ym1, and FIZZ1 (also referred to as RELMα) responses in the tissues. A similarly impaired Th2 response was observed following N. brasiliensis infection. In vitro, IL-21 significantly augmented IL-4Rα and IL-13Rα1 expression in macrophages, resulting in increased FIZZ1 mRNA and arginase-1 activity following stimulation with IL-4 and IL-13. As such, these data identify the IL-21R as an important amplifier of alternative macrophage activation. Collectively, these results illustrate an essential function for the IL-21R in the development of pathogen-induced Th2 responses, which may have relevance in therapies for both inflammatory and chronic fibrotic diseases.

This publication has 59 references indexed in Scilit: