IL-13Rα2 and IL-10 coordinately suppress airway inflammation, airway-hyperreactivity, and fibrosis in mice
Mark S. Wilson, … , Allen W. Cheever, Thomas A. Wynn
Mark S. Wilson, … , Allen W. Cheever, Thomas A. Wynn
Published October 1, 2007
Citation Information: J Clin Invest. 2007;117(10):2941-2951. https://doi.org/10.1172/JCI31546.
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Research Article Immunology

IL-13Rα2 and IL-10 coordinately suppress airway inflammation, airway-hyperreactivity, and fibrosis in mice

Abstract

Development of persistent Th2 responses in asthma and chronic helminth infections are a major health concern. IL-10 has been identified as a critical regulator of Th2 immunity, but mechanisms for controlling Th2 effector function remain unclear. IL-10 also has paradoxical effects on Th2-associated pathology, with IL-10 deficiency resulting in increased Th2-driven inflammation but also reduced airway hyperreactivity (AHR), mucus hypersecretion, and fibrosis. We demonstrate that increased IL-13 receptor α 2 (IL-13Rα2) expression is responsible for the reduced AHR, mucus production, and fibrosis in BALB/c IL-10–/– mice. Using models of allergic asthma and chronic helminth infection, we demonstrate that IL-10 and IL-13Rα2 coordinately suppress Th2-mediated inflammation and pathology, respectively. Although IL-10 was identified as the dominant antiinflammatory mediator, studies with double IL-10/IL-13Rα2–deficient mice illustrate an indispensable role for IL-13Rα2 in the suppression of AHR, mucus production, and fibrosis. Thus, IL-10 and IL-13Rα2 are both required to control chronic Th2-driven pathological responses.

Authors

Mark S. Wilson, Eldad Elnekave, Margaret M. Mentink-Kane, Marcus G. Hodges, John T. Pesce, Thirumalai R. Ramalingam, Robert W. Thompson, Masahito Kamanaka, Richard A. Flavell, Andrea Keane-Myers, Allen W. Cheever, Thomas A. Wynn

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Figure 1

Th2-polarized SEA-induced airway inflammation.

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Th2-polarized SEA-induced airway inflammation. Animals were sensitized w...
Animals were sensitized with 10 μg SEA on days 1 and 14, followed by 2 intratracheal airway challenges with 10 μg SEA on days 28 and 31. Animals were euthanized 24 hours after the final airway challenge. *P < 0.05, Mann-Whitney U test. (A) Total airway infiltrates and airway eosinophilia recovered in BAL. (B) BAL fluid eotaxin levels measured by ELISA. (C) BAL fluid IL-5 levels measured by ELISA. (D) Lung tissue mRNA, IFNγ (Th1) and IL-4 (Th2). (E) BAL and lung cells stimulated with PMA and ionomycin with brefeldin A for 3 hours and then stained with anti-CD4 (APC) and anti-IL-13 (PE) before acquisition and analysis by FACS. (F) Five-micrometer sections were cut from paraffin-embedded lung tissue and stained with H&E (lower panels) to show cellular infiltration or alcian blue–PAS (upper panels) showing mucin+ goblet cells lining the airways. The mucin response to SEA was 7+, while the inflammatory response to PBS was 2+ and to SEA, 4+. Five lungs from each group were scored in a blinded fashion; original magnification, ×100. (G) Lung cells and BAL recoveries from C57BL/6 IL-10–GFP mice were stained with anti-CD4 (APC) and anti-CD25 (PE) for lung cells, with GFP expression observed in the FL1 channel. (H) RNA was extracted from lung tissue, with IL-13Rα2 mRNA quantified by quantitative reverse transcription PCR (qRT-PCR). (I) Soluble IL-13Rα2 was measured by ELISA, in serum collected from mice bled 24 hours after the last airway challenge.