RT Journal Article SR Electronic T1 SOCS-1 inhibition of type I interferon limits Staphylococcus aureus skin host defense JF bioRxiv FD Cold Spring Harbor Laboratory SP 2020.09.28.317107 DO 10.1101/2020.09.28.317107 A1 Nathan Klopfenstein A1 Stephanie Brandt A1 Sydney Castellanos A1 C. Henrique Serezani YR 2020 UL http://biorxiv.org/content/early/2020/09/28/2020.09.28.317107.abstract AB The innate immune response to methicillin-resistant Staphylococcus aureus (MRSA) skin infection culminates in forming an abscess that prevents the bacterial spread and tissue damage. Pathogen recognition receptors (PRRs) dictate the balance between microbial control and tissue damage. Therefore, intracellular brakes are of fundamental importance to tune the appropriate host defense while preventing injury. The intracellular inhibitor suppressor of cytokine signaling 1 (SOCS-1); is a classic JAK/STAT inhibitor that prevents PRR responses by influencing the expression and actions of PRR adaptors and downstream effectors. Whether SOCS-1 is a molecular component of skin host defense remains to be determined. Here, we hypothesized that SOCS-1 decreases type I interferon production and IFNAR-mediated antimicrobial effector functions of the inflammatory response during MRSA skin infection. Our data show that MRSA skin infection enhances SOCS-1 expression, and both SOCS-1 inhibitor peptide treated and myeloid-specific SOCS-1 deficient mice display decreased lesion size, bacterial loads, and increased abscess thickness when compared to wild-type mice treated or not with scrambled peptide control. SOCS-1 deletion/inhibition increases phagocytosis and bacterial killing, dependent on nitric oxide release. SOCS-1 inhibition also increases antimicrobial effector function correlated with type I and type II interferon levels in vivo. IFNAR deletion and antibody blockage abolished the beneficial effects of SOCS-1 inhibition in vivo. Notably, we unveiled that hyperglycemia triggers aberrant SOCS-1 expression that correlates with decreased overall IFN signatures in the skin. SOCS-1 inhibition restores skin host defense in highly susceptible hyperglycemic mice. Overall, these data demonstrate a role for type I interferons in enhancing microbial clearance and host defense during MRSA skin infection.Competing Interest StatementThe authors have declared no competing interest.