The Keenan Research Centre for Biomedical Science, Unity Health Toronto, Toronto, Canada; Department of Laboratory Medicine & Pathobiology, Medical Sciences Building, University of Toronto, Toronto, Canada
Johannes Westman
Cell Biology Program, The Hospital for Sick Children Research Institute, Toronto, Canada
Dustin A Ammendolia
Cell Biology Program, The Hospital for Sick Children Research Institute, Toronto, Canada; Department of Molecular Genetics, Medical Sciences Building, University of Toronto, Toronto, Canada
Fatemeh Mirshafiei Langari
Program in Molecular Medicine, The Hospital for Sick Children Research Institute, Toronto, Canada; Department of Biochemistry, Medical Sciences Building, University of Toronto, Toronto, Canada
Noah Fine
Faculty of Dentistry, University of Toronto, Toronto, Canada
Nicole Toepfner
Department of Pediatrics, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
Zhubing Li
Cell Biology Program, The Hospital for Sick Children Research Institute, Toronto, Canada
Manraj Sharma
Cell Biology Program, The Hospital for Sick Children Research Institute, Toronto, Canada
Judah Glogauer
Cell Biology Program, The Hospital for Sick Children Research Institute, Toronto, Canada; Faculty of Dentistry, University of Toronto, Toronto, Canada
Mariana I Capurro
Cell Biology Program, The Hospital for Sick Children Research Institute, Toronto, Canada
Nicola L Jones
Cell Biology Program, The Hospital for Sick Children Research Institute, Toronto, Canada; Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children, Toronto, Canada; Department of Physiology, Medical Sciences Building, University of Toronto, Toronto, Canada; Department of Paediatrics, Temerty Faculty of Medicine, University of Toronto, Toronto, Canada
Program in Molecular Medicine, The Hospital for Sick Children Research Institute, Toronto, Canada; Department of Anesthesia and Pain Medicine, The Hospital for Sick Children, Toronto, Canada; Department of Anesthesiology & Pain Medicine, Temerty Faculty of Medicine, University of Toronto, Toronto, Canada
Warren L Lee
The Keenan Research Centre for Biomedical Science, Unity Health Toronto, Toronto, Canada; Department of Laboratory Medicine & Pathobiology, Medical Sciences Building, University of Toronto, Toronto, Canada; Department of Biochemistry, Medical Sciences Building, University of Toronto, Toronto, Canada; Department of Medicine and Interdepartmental Division of Critical Care Medicine, Temerty Faculty of Medicine, University of Toronto, Toronto, Canada
Michael Glogauer
Faculty of Dentistry, University of Toronto, Toronto, Canada; Department of Dental Oncology and Maxillofacial Prosthetics, University Health Network, Princess Margaret Cancer Centre, Toronto, Canada; Centre for Advanced Dental Research and Care, Mount Sinai Hospital, Toronto, Canada
Cell Biology Program, The Hospital for Sick Children Research Institute, Toronto, Canada; The Keenan Research Centre for Biomedical Science, Unity Health Toronto, Toronto, Canada; Department of Biochemistry, Medical Sciences Building, University of Toronto, Toronto, Canada
Cell Biology Program, The Hospital for Sick Children Research Institute, Toronto, Canada; Department of Paediatrics, Temerty Faculty of Medicine, University of Toronto, Toronto, Canada; Institute of Medical Science, University of Toronto, Medical Sciences Building, University of Toronto, Toronto, Canada; Division of Nephrology, The Hospital for Sick Children, Toronto, Canada
Neutrophils are essential for host defense against Staphylococcus 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 extracellular S. aureus more 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 the exocytosis of neutrophil secondary granules. In a murine model of S. aureus skin and soft tissue infection (SSTI), local SLIT2 levels fall initially but increase subsequently, peaking at 3 days after infection. Of note, the neutralization of endogenous SLIT2 worsens SSTI. Temporal fluctuations in local 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 to S. aureus.
