LTB4 actions in infected apoptotic cells clearance during Staphylococcus aureus skin infection in diabetic mice.

Abstract

Type 1 diabetes (T1D) is an autoimmune disease characterized by destruction of pancreatic beta cells and high glucose levels. Diabetes has been associated with several inflammatory complications: impaired antimicrobial function and poor chemotaxis of phagocytes have been associated with increased risk of infections. Staphylococcus aureus is a major cause of skin and soft tissue infections in diabetic patients, mainly caused by community-acquired methicillin-resistant S. aureus (MRSA). During MRSA infection, neutrophils migrate to the affected tissue, engulf and kill pathogens and become apoptotic. Dying cells start secreting "find-me" signals that recruit monocytes and macrophages to the site of infection to help eliminate apoptotic cells and restore homeostasis. However, defective phagocytosis of dead cell results on the formation of secondary necrotic cells, followed by the release of damage-associated molecular patterns (DAMPs). Recent preliminary results from Dr. Serezani's laboratory identified IL-33 as a highly abundant cytokine in the skin of MRSA-infected diabetic mice. IL-33 is a DAMP since it is produced/secreted by dead cells. Furthermore, his group has shown that diabetic mice produce aberrant amounts of the lipid mediator leukotriene B4 (LTB4) in the skin of MRSA-infected diabetic mice. Studies have shown that aberrant LTB4 production can influence negatively chronic diseases, by maintaining cellular migration and intracellular inflammatory programs in neutrophils, monocytes/macrophages. Thus, the hypothesis of this work is that LTB4 induces prolonged and deleterious inflammatory response observed during skin infection in diabetic mice stems that promote accumulation of necrotic cell and release of DAMPs, including IL-33 that causes tissue injury and impairs skin host defense in diabetic mice.