Aberrant innate immune response to Leishmania major in the absence of secretory leukocyte protease inhibitor (SLPI) (37.38)

Abstract

Abstract Resistance to intracellular pathogens such as leishmania relies upon both innate and adaptive immune responses. Overexuberant host responses can lead to uncontrolled inflammation, highlighting a critical need for suppressive mechanisms to limit tissue damage. SLPI is an epithelial-derived protease inhibitor with anti-microbial and anti-inflammatory functions and is inducible in rodent phagocytes. Moreover, SLPI is induced by L. major and increased SLPI expression is evident within lesions following local infection with L. major. While resistance in C57Bl/6 mice is attributed to IFNγ-dominant Th1 responses, SLPI-deficient C57Bl/6 mice also develop strong Th1 responses, yet infection with L. major rapidly rages out of control with progression to systemic disease. To determine the mechanism of this dysregulated response, we infected SLPI-deficient and wildtype phagocytes with L. major and detected increased levels of inducible NO synthase (iNOS) and myeloperoxidase (MPO) coincident with altered arginase expression in the absence of SLPI. Intradermal infection with L. major revealed a rapid influx of phagocytes and modulation of iNOS, MPO and arginase. However, despite persistence of activated phagocytic cells, SLPI-deficient mice fail to resolve the inflammation or clear the infection. Our results define a novel contribution of SLPI to innate host defense against intracellular parasites and its potential use to hasten resolution of infection and inflammatory pathogenesis.