The chemorepellent, SLIT2, bolsters innate immunity againstStaphylococcus aureus

AbstractNeutrophils are essential for host defense againstStaphylococcus aureus(S. aureus). The neuro-repellent, SLIT2, potently inhibits neutrophil chemotaxis, and might therefore be expected to impair antibacterial responses. We report here that, unexpectedly, neutrophils exposed to the N-terminal SLIT2 (N-SLIT2) fragment kill extracellularS. aureusmore efficiently. N-SLIT2 amplifies reactive oxygen species production in response to the bacteria by activating p38 mitogen-activated protein kinase that in turn phosphorylates NCF1, an essential subunit of the NADPH oxidase complex. N-SLIT2 also enhances exocytosis of secondary granules. In a murine model ofS. aureusskin and soft tissue infection (SSTI), local SLIT2 levels fall initially but increase subsequently, peaking ≈ 3 days after infection. Of note, neutralization of endogenous SLIT2 worsens SSTI. Temporal fluctuations in tissue SLIT2 levels may promote neutrophil recruitment and retention at the infection site and hasten bacterial clearance by augmenting neutrophil oxidative burst and degranulation. Collectively, these actions of SLIT2 coordinate innate immune responses to limit susceptibility toS. aureus.One-sentence summarySLIT2, a prototypic neuro-repellent, spatiotemporally coordinates host defense againstStaphylococcus aureusinfection.