Phagocyte-derived SOCS1 disrupts Staphylococcus aureus skin host defense

Abstract

Abstract Methicillin-resistant Staphylococcus aureus (MRSA) skin infection is controlled by the actions of skin resident macrophages and the formation of a neutrophilic abscess that prevents bacterial spread and tissue damage. We and others have shown that myeloid differentiation factor 88 (MyD88) is required for the clearance of MRSA skin infection in mice. MyD88 expression is controlled by the balance between STAT1 and the suppressor of cytokine signaling 1 (SOCS1). Here, we hypothesized that SOCS1 inhibits antimicrobial effector functions and the inflammatory response, leading to poor abscess formation and tissue injury during MRSA skin infection. Our data show that MRSA skin infection enhances SOCS1 expression. Infection in myeloid-specific SOCS1 deficient mice displays decreased lesion size, lower bacterial loads, and increased abscess thickness when compared to WT mice. When we treated infected mice with a peptide that specifically inhibits the kinase inhibitory region (KIR) of SOCS1, it also improved infection outcome. Examining the mechanisms by which SOCS1 enhanced skin host defense, we observed increased phagocytosis and bacterial killing in SOCS1 deficient macrophages and KIR peptide-treated cells. Increased antimicrobial effector function correlated with enhanced STAT1 activation and increased production of IFNγ in vivo and in vitro. Next we tested whether IFNγ is crucial to improved host defense in KIR-treated mice. Our data show that the beneficial effect of SOCS1 KIR peptide in skin host defense was abrogated in mice treated with an IFNR blocking antibody and in the IFNR deficient mice. Overall, these data show that preventing SOCS1 actions enhances microbial clearance and host defense during MRSA skin infection.