Abstract
Abstract Regulation of the actin cytoskeleton is essential to multiple immune cell functions, including cell motility, adhesion, and activation. In lymphocytes, the actin-bundling protein L-plastin (LPL) plays critical roles in sustaining cell polarization and formation of the immunological synapse. We now show defects in the innate immune system that lead to profound susceptibility to pulmonary pneumococcal infection. LPL is required for generation of alveolar macrophages: there are fewer alveolar macrophages in the bronchoalveolar lavage fluid of LPL-/- mice, and regeneration of alveolar macrophages following sublethal irradiation is delayed when bone marrow is donated by LPL-/- mice. Activation of LPL-/- alveolar macrophages is also defective, with reduced upregulation of IL-1-beta and IL-6 following LPS stimulation. Reduced numbers and activation of alveolar macrophages in LPL-/- mice correlate with disrupted podosome formation. Reduced numbers and activation of alveolar macrophages would be expected to result in an inability to clear pulmonary pathogens. When challenged with pulmonary infection with pneumococcus, LPL-/- mice show a clearance defect within 3 hours, with a ten-fold increase in recoverable pneumococci compared to wild-type mice. LPL-/- mice thus offer a model system in which to detail how actin cytoskeletal integrity regulates macrophage development and activation.
Published Version
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