IL-4Rα-responsive smooth muscle cells contribute to initiation of TH2 immunity and pulmonary pathology in Nippostrongylus brasiliensis infections

Horsnell, W.G.C.;Vira, A.;Kirstein, F.;Mearns, H.;Hoving, J.C.;Cutler, A.J.;Dewals, B.;Myburgh, E.;Kimberg, M.;Arendse, B.;White, N.;Lopata, A.;Burger, P.E.;Brombacher, F.

Ludwig Lopata

Abstract

Nippostrongylus brasiliensis infections generate pulmonary pathologies that can be associated with strong TH2 polarization of the host's immune response. We present data demonstrating N. brasiliensis-driven airway mucus production to be dependent on smooth muscle cell interleukin 4 receptor-α (IL-4Rα) responsiveness. At days 7 and 10 post infection (PI), significant airway mucus production was found in IL-4Rα−/lox control mice, whereas global knockout (IL-4Rα−/−) and smooth muscle-specific IL-4Rα-deficient mice (SM-MHCCre IL-4Rα−/lox) showed reduced airway mucus responses. Furthermore, interleukin (IL)-13 and IL-5 cytokine production in SM-MHCCre IL-4Rα−/lox mice was impaired along with a transient reduction in T-cell numbers in the lung. In vitro treatment of smooth muscle cells with secreted N. brasiliensis excretory–secretory antigen (NES) induced IL-6 production. Decreased protein kinase C (PKC)-dependent smooth muscle cell proliferation associated with cell cycle arrest was found in cells stimulated with NES. Together, these data demonstrate that both IL-4Rα and NES-driven responses by smooth muscle cells make important contributions in initiating TH2 responses against N. brasiliensis infections.

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Mucosal Immunology

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1935-3456

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Nature Publishing Group

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DOI

10.1038/mi.2010.46