The IL-21 receptor augments Th2 effector function and alternative macrophage activation.
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 RELMalpha) responses in the tissues. A similarly impaired Th2 response was observed following N. brasiliensis infection. In vitro, IL-21 significantly augmented IL-4Ralpha and IL-13Ralpha1 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.
Pesce
John
J
Immunopathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, Bethesda, Maryland 20892, USA.
Kaviratne
Mallika
M
Ramalingam
Thirumalai R
TR
Thompson
Robert W
RW
Urban
Joseph F
JF
Cheever
Allen W
AW
Young
Deborah A
DA
Collins
Mary
M
Grusby
Michael J
MJ
Wynn
Thomas A
TA
D000818:Animals; D016207:Cytokines / Q000276:immunology; D005260:Female; D053738:Interleukin-21 Receptor alpha Subunit; D007378:Interleukins / Q000276:immunology; D008168:Lung / Q000033:anatomy & histology / Q000276:immunology / Q000469:parasitology; D008198:Lymph Nodes / Q000276:immunology; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009559:Nippostrongylus / Q000276:immunology; D018123:Receptors, Interleukin / Q000235:genetics / Q000276:immunology*; D053655:Receptors, Interleukin-21; D012550:Schistosoma mansoni / Q000276:immunology; D012555:Schistosomiasis mansoni / Q000276:immunology; D015398:Signal Transduction / Q000502:physiology; D017206:Strongylida Infections / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology*; D000098546:Interleukin-21
D016207:Cytokines; C508118:Il21r protein, mouse; D053738:Interleukin-21 Receptor alpha Subunit; D007378:Interleukins; D018123:Receptors, Interleukin; D053655:Receptors, Interleukin-21; D000098546:Interleukin-21