Leukotriene B4 levels determine staphylococcus aureus skin infection outcome

Abstract

Methicillin-resistant Staphylococcus aureus (MRSA) is a major cause of severe skin infections and due to antibiotic resistance there is an intrinsic need to develop new immunotherapeutic strategies. Skin immune responses to infections require the cross-talk between phagocytes and structural cells that involves the secretion of cytokines, chemokines, and lipids. Leukotriene B4 (LTB4) is a pleiotropic lipid mediator known as a chemoattractant, but is also necessary to promote antimicrobial activity through B leukotriene receptor 1 (BLT1) signaling. However, chronic LTB4 production is associated with inflammatory diseases, including diabetes. People with diabetes are more susceptible to infections. The determinants by which LTB4/BLT1 promotes protective or detrimental immune responses in homeostasis and diabetes are unknown. We hypothesize that LTB4 levels determine infection outcome; while LTB4 is necessary for infection control, excessive LTB4 levels promote overwhelming inflammation that impairs host defense. Our data show that skin macrophages were necessary for LTB4 production and that LTB4 was vital for neutrophil direction, abscess formation, IL 1β production, and MRSA clearance through reactive oxygen species production. Importantly, topical LTB4 ointment treatment enhances neutrophil direction, abscess formation, and bacterial clearance. Conversely, in the setting of diabetes, skin macrophages drove excessive LTB4 production that promoted overwhelming inflammation, uncontrolled neutrophil recruitment, poor abscess formation, and lack of bacterial control. Diabetic mice treated with a topical ointment to inhibit BLT1 dampened inflammation and restored host defense by improving abscess formation, bacterial clearance, and overall inflammatory responses in the skin. These data demonstrate the balance of LTB4-induced inflammation is critical for regulating optimal immune responses during infections. This work highlights the importance of investigating the role of inflammatory mediators in the settings of health and disease. Targeting LTB4/BLT1 has therapeutic potential to regulate inflammation during MRSA skin infection by enhancing immune responses in settings of vulnerability or decrease inflammation in diabetes.