SOCS-1 inhibition of type I interferon restrains Staphylococcus aureus skin host defense

Author summary The control of Staphylococcus aureus skin and soft tissue infections is dictated by the balance between pro- and anti-inflammatory actions in phagocytes and structural cells. Although most studies have focused on the actions of inflammatory mediators, the role of intracellular effectors that shape innate immune response during skin infection is not well understood. Here, we identified a heretofore unknown role of the intracellular negative regulator of the immune response suppressor of cytokine signaling 1 (SOCS-1) in the control of S. aureus skin infection. Myeloid-specific SOCS-1 expression is detrimental to skin infection by inhibiting type I interferon (IFN)-dependent nitric oxide production and bacterial killing. A SOCS-1 blocking peptide greatly increases skin host defense. Importantly, we linked increased SOCS-1 expression to impaired host defense in a model of hyperglycemia. Transcriptomic analysis showed overall decreased expression of IFN-related genes and genetic and pharmacological SOCS-1 blockage restored skin host defense in hyperglycemic mice. Together, our work demonstrates a previously undocumented detrimental role for SOCS1-dependent skin host defense and suggests that blocking SOCS-1 might enable the host to efficiently control infection in both homeostatic and hyperglycemic conditions. The skin innate immune response to methicillin-resistant Staphylococcus aureus (MRSA) culminates in the formation of an abscess to prevent bacterial spread and tissue damage. Pathogen recognition receptors (PRRs) dictate the balance between microbial control and injury. Therefore, intracellular brakes are of fundamental importance to tune the appropriate host defense while inducing resolution. The intracellular inhibitor suppressor of cytokine signaling 1 (SOCS-1), a known JAK/STAT inhibitor, prevents 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. We hypothesized that SOCS-1 decreases type I interferon production and IFNAR-mediated antimicrobial effector functions, limiting the inflammatory response during 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 with the scrambled peptide control. SOCS-1 deletion/inhibition increases phagocytosis and bacterial killing, dependent on nitric oxide release. SOCS-1 inhibition also increases the levels of 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 infected skin. SOCS-1 inhibition restores skin host defense in the highly susceptible hyperglycemic mice. Overall, these data demonstrate a role for SOCS-1-mediated type I interferon actions in host defense and inflammation during MRSA skin infection.

Automated summary

SOCS-1 plays a role in controlling Staphylococcus aureus skin infection and is associated with decreased host defense under hyperglycemic conditions. Blocking SOCS-1 may enhance skin host defense. Furthermore, SOCS-1 inhibition promotes skin host defense by increasing levels of type I interferon.