A MyD88–JAK1–STAT1 complex directly induces SOCS-1 expression in macrophages infected with Group A Streptococcus

Abstract

Some pathogens can use host suppressor of cytokine signaling 1 (SOCS-1), an important negative-feedback molecule, as the main mode of immune evasion. Here we found that group A Streptococcus (GAS) is capable of inducing SOCS-1 expression in RAW264.7 and BMDM macrophages. IFN-b plays a role in GAS-induced SOCS-1 expression in macrophages following the induction of cytokine expression by GAS, representing the classical pathway of SOCS-1 expression. However, GAS also induced STAT1 activation and SOCS-1 expression when GAS-infected cells were incubated with anti-IFN-b monoclonal antibody in this study. Moreover, upon comparing TLR4 2/2 BMDM macrophages with wild-type (WT) cells, we found that TLR4 also plays an essential role in the induction of SOCS-1. MyD88, which is an adaptor protein for TLR4, contributes to STAT1 activation and phosphorylation by forming a complex with Janus kinase 1 (JAK1) and signal transducer and activator of transcription 1 (STAT1) in macrophages. GAS-stimulated expression of STAT1 was severely impaired in MyD88 2/2 macrophages, whereas expression of JAK1 was unaffected, suggesting that MyD88 was involved in STAT1 expression and phosphorylation. Together, these data demonstrated that in addition to IFN-b signaling and MyD88 complex formation, JAK1 and STAT1 act in a novel pathway to directly induce SOCS-1 expression in GAS-infected macrophages, which may be more conducive to rapid bacterial infection.

Properties of STAT1 and IRF1 enhancers and the influence of SNPs

“…To further test this notion we performed additional assessment of SOCS1 , a key negative regulator of IFNγ signaling that is responsive to IFNs and other immune signaling pathways [31, 32]. SOCS1 responds to IFNγ in HeLa cells (Fig.…”

Socs1 and Socs3 degrades Traf6 via polyubiquitination in LPS-induced acute necrotizing pancreatitis

“…A group of intracellular immune regulators, the suppressor of cytokine signaling (Socs) protein family, has been shown to negatively regulate TLR signaling via the modulation of signal transducer and activator of transcription (STAT) pathway. 12 , 13 There are eight members in the Socs family: Socs1 to Socs7 and cytokine-inducible Src homology 2 (SH2)-containing protein (Cis). Structurally, they all have a central SH2 domain and a C-terminal conserved domain termed the Socs box.…”

SOCS-1 inhibition of type I interferon limitsStaphylococcus aureusskin host defense

“…SOCS-1 is a pleiotropic inhibitor of both the innate and adaptive immune response by controlling the actions of transcription factors and signaling effectors downstream of cytokine receptors, growth factors, and PRRs. We and others have shown that SOCS-1 inhibits MyD88 expression and actions (Serezani et al, 2011;Wu et al, 2015;Zahoor et al, 2020). SOCS-1 can prevent the differentiation of "pro-inflammatory" or M1 macrophages by limiting NF-κB p65 activation and STAT-1 actions (Duncan et al, 2017).…”

“…Therefore, given the role of TLRs and inflammatory cytokines in in vivo host defense, it is anticipated that endogenous SOCS-1 might help prevent tissue damage and, consequently, impacts phagocyte antimicrobial effector function. Indeed, infections with both gram-positive (Mancuso et al, 2007;Wu et al, 2015), gram-negative (Decker et al, 2005) bacteria as well as Mycobacterium tuberculosis (Manca et al, 2005) and parasites, such as Leishmania major (Bullen et al, 2003) and the fungus Candida albicans (Shi et al, 2018) promote SOCS-1 expression to actively suppress the immune response, allowing pathogen replication and immune evasion. Expression of SOCS-1 during infection correlates with reduced levels of the pro-inflammatory cytokines IL-1β, TNF-α, and IL-6 as well as antimicrobial NO and reactive oxygen species (ROS) (Duncan et al, 2017;Yoshimura et al, 2007).…”