Macrophage-derived LTB4 promotes abscess formation and clearance of Staphylococcus aureus skin infection in mice

• Published in: PLoS pathogens 2018-08, Vol.14 (8), p.e1007244-e1007244
• Main Authors: Brandt, Stephanie L, Klopfenstein, Nathan, Wang, Soujuan, Winfree, Seth, McCarthy, Brian P, Territo, Paul R, Miller, Lloyd, Serezani, C Henrique
• Format: Article
• Language: English
• Subjects: Abscess - genetics; Abscess - immunology; Abscess - microbiology; Abscess - pathology; Animals; Antibiotics; Antiinfectives and antibacterials; Arachidonate 5-lipoxygenase; Arachidonate 5-Lipoxygenase - genetics; Bacteria; Bacterial Load - genetics; Bacterial Load - immunology; Biology and life sciences; Cells, Cultured; Chemokines; Chemotactic factors; Chemotaxis; Cytokines; Dermatology; Drug resistance; Female; G protein-coupled receptors; Immune clearance; Immune response; Immune system; Immunology; Infections; Infectious diseases; Inflammation; Innate immunity; Leukocytes (neutrophilic); Leukotriene B4; Leukotriene B4 - metabolism; Leukotriene B4 - physiology; Lipids; Lipoxygenase; Macrophages; Macrophages - immunology; Macrophages - metabolism; Male; Medicine; Medicine and Health Sciences; Methicillin; Methicillin-Resistant Staphylococcus aureus - growth & development; Methicillin-Resistant Staphylococcus aureus - immunology; Mice; Mice, Inbred C57BL; Mice, Knockout; Microorganisms; Microscopy; Monocytes; Neutrophils; Ointments; Pathogens; Phagocytes; Reactive oxygen species; Receptors; Receptors, Leukotriene B4 - genetics; Sepsis; Skin; Staphylococcal Skin Infections - genetics; Staphylococcal Skin Infections - immunology; Staphylococcal Skin Infections - pathology; Staphylococcus aureus; Staphylococcus infections; Streptococcus infections
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1007244

The early events that shape the innate immune response to restrain pathogens during skin infections remain elusive. Methicillin-resistant Staphylococcus aureus (MRSA) infection engages phagocyte chemotaxis, abscess formation, and microbial clearance. Upon infection, neutrophils and monocytes find a gradient of chemoattractants that influence both phagocyte direction and microbial clearance. The bioactive lipid leukotriene B4 (LTB4) is quickly (seconds to minutes) produced by 5-lipoxygenase (5-LO) and signals through the G protein-coupled receptors LTB4R1 (BLT1) or BLT2 in phagocytes and structural cells. Although it is known that LTB4 enhances antimicrobial effector functions in vitro, whether prompt LTB4 production is required for bacterial clearance and development of an inflammatory milieu necessary for abscess formation to restrain pathogen dissemination is unknown. We found that LTB4 is produced in areas near the abscess and BLT1 deficient mice are unable to form an abscess, elicit neutrophil chemotaxis, generation of neutrophil and monocyte chemokines, as well as reactive oxygen species-dependent bacterial clearance. We also found that an ointment containing LTB4 synergizes with antibiotics to eliminate MRSA potently. Here, we uncovered a heretofore unknown role of macrophage-derived LTB4 in orchestrating the chemoattractant gradient required for abscess formation, while amplifying antimicrobial effector functions.