title: CD36 Is Essential for Regulation of the Host Innate Response to Staphylococcus aureus α-Toxin-Mediated Dermonecrosis.
abstract: Staphylococcus aureus is the primary cause of skin and skin structure infections (SSSIs) in the United States. α-Hemolysin (Hla), a pore-forming toxin secreted by S. aureus and a major contributor to tissue necrosis, prompts recruitment of neutrophils critical for host defense against S. aureus infections. However, the failure to clear apoptotic neutrophils can result in damage to host tissues, suggesting that mechanisms of neutrophil clearance are essential to limiting Hla-mediated dermonecrosis. We hypothesized that CD36, a scavenger receptor which facilitates recognition of apoptosing cells, would play a significant role in regulating Hla-mediated inflammation and tissue injury during S. aureus SSSI. In this study, we show that CD36 on macrophages negatively regulates dermonecrosis caused by Hla-producing S. aureus. This regulation is independent of bacterial burden, as CD36 also limits dermonecrosis caused by intoxication with sterile bacterial supernatant or purified Hla. Dermonecrotic lesions of supernatant intoxicated CD36(-/-) mice are significantly larger, with increased neutrophil accumulation and IL-1β expression, compared with CD36(+/+) (wild-type) mice. Neutrophil depletion of CD36(-/-) mice prevents this phenotype, demonstrating the contribution of neutrophils to tissue injury in this model. Furthermore, administration of CD36(+/+) but not CD36(-/-) macrophages near the site of intoxication reduces dermonecrosis, IL-1β production and neutrophil accumulation to levels seen in wild-type mice. This therapeutic effect is reversed by inhibiting actin polymerization in the CD36(+/+) macrophages, supporting a mechanism of action whereby CD36-dependent macrophage phagocytosis of apoptotic neutrophils regulates Hla-mediated dermonecrosis. Taken together, these data demonstrate that CD36 is essential for controlling the host innate response to S. aureus skin infection.
authors.affiliation: Department of Pharmaceutical Sciences, University of New Mexico College of Pharmacy, Albuquerque, NM 87131; and.
authors.forename: Moriah J
authors.initials: MJ
authors.lastname: Castleman
authors.affiliation: School of Dentistry, University of Alberta, Edmonton, Alberta T6G 2E1, Canada.
authors.forename: Maria
authors.initials: M
authors.lastname: Febbraio
authors.affiliation: Department of Pharmaceutical Sciences, University of New Mexico College of Pharmacy, Albuquerque, NM 87131; and phall@salud.unm.edu.
authors.forename: Pamela R
authors.initials: PR
authors.lastname: Hall
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology; D001427:Bacterial Toxins / Q000276:immunology*; D015153:Blotting, Western; D018955:CD36 Antigens / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D004195:Disease Models, Animal; D005434:Flow Cytometry; D006460:Hemolysin Proteins / Q000276:immunology*; D054884:Host-Pathogen Interactions / Q000276:immunology; D007113:Immunity, Innate / Q000235:genetics / Q000276:immunology*; D053583:Interleukin-1beta / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism; D010587:Phagocytosis / Q000276:immunology; D051116:Receptors, Scavenger / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017192:Skin Diseases, Bacterial / Q000235:genetics / Q000276:immunology* / Q000382:microbiology; D013203:Staphylococcal Infections / Q000235:genetics / Q000276:immunology* / Q000382:microbiology; D013211:Staphylococcus aureus / Q000276:immunology / Q000502:physiology
chemical_list: D001427:Bacterial Toxins; D018955:CD36 Antigens; D006460:Hemolysin Proteins; D053583:Interleukin-1beta; D051116:Receptors, Scavenger; C021091:staphylococcal alpha-toxin