IL-4R alpha-responsive smooth muscle cells contribute to initiation of T(H)2 immunity and pulmonary pathology in Nippostrongylus brasiliensis infections

Nippostrongylus brasiliensis infections generate pulmonary pathologies that can be associated with strong T(H)2 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-alpha (IL-4R alpha) responsiveness. At days 7 and 10 post infection (PI), significant airway mucus production was found in IL-4R alpha(-/lox) control mice, whereas global knockout (IL-4R alpha(-/-)) and smooth muscle-specific IL-4R alpha-deficient mice (SM-MHCCre IL-4R alpha(-/lox)) showed reduced airway mucus responses. Furthermore, interleukin (IL)-13 and IL-5 cytokine production in SM-MHCCre IL-4R alpha(-/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-4R alpha and NES-driven responses by smooth muscle cells make important contributions in initiating T(H)2 responses against N. brasiliensis infections.