Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea Songpa-gu, Seoul-t'ukpyolsi, Republic of Korea
Abstract Text: Macrophages primarily function in the detection of infection or tissue injury to induce immune responses. However, little is known about the signaling factors that regulate their action and thereby control inflammatory responses. We show here that the neuronal guidance factor SLIT3 is induced by bacterial lipopolysaccharide (LPS) through toll-like receptor 4 (TLR4) activation in bone marrow macrophages. Depleted SLIT3 suppressed the augmented phagocytic activity of macrophages in LPS response and their anti-microbial effects in vitro. A SLIT3 deficiency also promoted a macrophage 1 (M1) profile accompanied by an upregulation of pro-inflammatory cytokines. SLIT3-deficient mice displayed increased M1 populations in peritoneal cells compared with wild-type mice upon LPS exposure. We determined whether a direct SLIT3 administration in vivo during endotoxemia by E. Coli bioparticles would control the inflammatory disease state. As expected, SLIT3-treated mice recovered from the acute endotoxic inflammatory response though enhanced phagocytosis by Gr-1+ granulocytes and F4/80+ macrophages. This diminished the deleterious aspects of the host response to the pathogen-induced cytokines IL-1β or IL-18 in the peritoneal lavage and blood. These findings suggest that SLIT3 regulates innate immunity in a manner relevant to inflammation, and that this may provide a potential treatment strategy for excessive inflammation or a sustained hyperinflammatory response.
