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
View: Text | PDF
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

×

Figure 2

Th2 cytokine production is reduced in the lungs of schistosome egg–challenged IL-21R–/– mice.

Options: View larger image (or click on image) Download as PowerPoint
Th2 cytokine production is reduced in the lungs of sc...
Groups of naive WT (white bars) and IL-21R–/– mice (gray bars) were i.v. challenged with live S. mansoni eggs and sacrificed on days 4, 7, and 14 after challenge. (A) RNA was prepared from lung tissues and analyzed individually (n = 5 per group/time point) by real-time RT-PCR. The top and bottom of the boxes indicate the seventy-fifth and twenty-fifth percentiles, respectively; the line within the box indicates the fiftieth percentile; and the top and bottom whiskers indicate the ninetieth and tenth percentiles, respectively, of the tested samples. ND, not detected. *P < 0.05, **P < 0.01, ***P < 0.001 versus WT. (B) Spleens (Spl) and lung-associated lymph nodes (LALN) were each pooled (2 separate groups, 3–4 mice per group), and single-cell suspensions were assayed for IL-5, IL-10, IL-13, and IFN-γ after a 72-hour incubation in the presence of Con A (1 mg/ml) or SEA (20 mg/ml). Results are mean ± SEM. Cytokines were below the level of detection in unstimulated cultures. (C) Granuloma size (volume, mm3 × 10–3) and the percentage of eosinophils in granulomas were quantified microscopically. (D) Real-time PCR analysis of Th2-regulated inflammatory genes in granulomatous lung tissue. All data are representative of at least 2 separate experiments.