The IL-21 receptor augments Th2 effector function and alternative macrophage activation
John Pesce, Mallika Kaviratne, Thirumalai R. Ramalingam, Robert W. Thompson, Joseph F. Urban, Allen W. Cheever, Deborah A. Young, Mary Collins, Michael J. Grusby, Thomas A. Wynn
John Pesce, Mallika Kaviratne, Thirumalai R. Ramalingam, Robert W. Thompson, Joseph F. Urban, Allen W. Cheever, Deborah A. Young, Mary Collins, Michael J. Grusby, Thomas A. Wynn
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Research Article Immunology

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

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.

Authors

John Pesce, Mallika Kaviratne, Thirumalai R. Ramalingam, Robert W. Thompson, Joseph F. Urban, Allen W. Cheever, Deborah A. Young, Mary Collins, Michael J. Grusby, Thomas A. Wynn

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Figure 8

IL-21 signaling promotes alternative macrophage activation by modulating IL-13R expression.

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IL-21 signaling promotes alternative macrophage activation by modulating...
Bone marrow–derived macrophages were treated with IL-21 (20 ng/ml), either alone or in combination with IL-4 (20 ng/ml) and IL-13 (20 ng/ml) overnight. In some experiments, macrophages were pretreated with IL-21 for 6 hours prior to IL-4 and IL-13 administration. Cells were lysed 20 hours later, and RNA was analyzed individually by real-time RT-PCR. (A) The ability of IL-21 to promote alternative macrophage activation was assessed by measuring Arg-1 and FIZZ1 mRNA expression. (B) Arginase activity was quantified in cell lysates by measuring the conversion of l-arginine to Urea (mg/dl ± SEM; triplicate measurements). (C) Expression of IL-4Rα and IL-13Rα1 mRNA was evaluated by real-time PCR. IL-13Rα2 mRNA was nearly undetectable in all conditions (not shown). The data shown in A, B, and C are representative of 3 separate experiments. (D) Naive C57BL/6 mice were challenged i.v. with 5,000 live S. mansoni eggs and treated with PBS or recombinant IL-21 (2 μg/dose) every other day from day 1 through day 6. Animals (n = 5 per group) were sacrificed on day 7, and lung IL-13Rα2 mRNA levels were assayed by real-time PCR and expressed as fold increase over untreated controls. Mice were also bled at the time of sacrifice, and the amount of sIL-13Rα2 in individual serum samples was assayed by ELISA. *P < 0.05; **P < 0.01; ***P < 0.001. Similar results were obtained in a separate study.