The suppressor of cytokine signaling 1 (SOCS1) impairs skin host defense in healthy and hyperglycemic mice

Abstract

Abstract Methicillin-resistant Staphylococcus aureus (MRSA) is a leading cause of skin and soft tissue infections in both healthy individuals and those with preexisting conditions such as diabetes. MRSA skin infections are characterized by the formation of a neutrophilic abscess that prevents bacterial spread to deeper tissues. Although we and others have shown that skin resident macrophages initiate this immune response, the molecular events that lead to optimal neutrophil recruitment and abscess formation remain to be fully elucidated. Here we examined the role of the protein SOCS1 and its impact on host defense during MRSA skin infection in both hyperglycemic and euglycemic mice. SOCS1 is a known STAT1 inhibitor and negatively influences TLR activation, possibly influencing early skin host defense. We have previously demonstrated that hyperglycemic mice are unable to control MRSA skin infection, which was accompanied by poor abscess formation. Here, we demonstrate that SOCS1 expression in macrophages isolated from infected hyperglycemic mice is greatly enhanced in a manner dependent on histone deacetyltransferase (HDAC) activity. Delivery of SOCS1 inhibitor peptide (iKIR) as well as myeloid cell-specific SOCS1 deletion decreased both lesion size and bacterial burden in the skin. SOCS1 inhibition enhanced the production of pro-inflammatory cytokines TNF-a and IL-1b. Importantly, SOCS1 inhibition enhanced bacterial ingestion and killing in macrophages from both euglycemic and hyperglycemic mice. Overall, these data indicate that the threshold of SOCS1 expression may negatively impact skin host defense in both hyperglycemic and other susceptible patient populations.