Aberrant localized LTB4 production exacerbates methicillin-resistant Staphylococcus aureus skin infection in diabetic mice

A major cause of severe skin infections is methicillin-resistant Staphylococcus aureus (MRSA). Immunotherapeutic strategies are needed to treat infections. Neutrophils and macrophages control MRSA skin infection but undue inflammation causes injury. The bioactive eicosanoid leukotriene B4 is a potent chemoattractant and enhances phagocyte effector functions in naïve mice. However we have shown that diabetic mice produce chronic LTB4 which promotes susceptibility to sepsis but the role of LTB4 in localized infections is unknown. We hypothesize that aberrant LTB4 drive excessive inflammation during MRSA skin infection in diabetics. Diabetic mice at day 1 post infection had larger infected areas, bacterial and apoptotic cell burdens than nondiabetic controls. By intravital microscopy we observed more neutrophil recruitment in diabetic mice. These effects correlated with high levels of LTB4 and its receptor BLT1. At day 9 post infection nondiabetic mice were nearly healed but diabetic mice still had cell infiltration, high bacterial and apoptotic burdens, which associated with high levels of inflammatory mediators. To test whether chronic LTB4 causes uncontrolled infection, diabetic mice were treated daily with a topical ointment containing BLT1 antagonist. The treatment reduced infection area, bacterial burden and neutrophil recruitment. We also detected fewer apoptotic cells and lower expression of inflammatory mediators. These findings reveal that LTB4 is detrimental for diabetics by chronically inducing a damaging inflammatory response. We observe that topical BLT1 antagonist treatment improves host defense in diabetic mice and promises to be an effective therapeutic to treat MRSA infections in diabetic patients.