SOCS-1 inhibition of type I interferon restrains Staphylococcus aureus skin host defense.
SOCS-1 inhibition of type I interferon restrains Staphylococcus aureus skin host defense.
复制标题
I型干扰素抑制SOCS-1抑制金黄色葡萄球菌皮肤宿主防御。
DOI：
10.1371/journal.ppat.1009387
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发表时间：
2021-03
期刊：
影响因子：
6.7
通讯作者：
Serezani CH
中科院分区：
文献类型：
--
作者：
Klopfenstein N;Brandt SL;Castellanos S;Gunzer M;Blackman A;Serezani CH
皮肤对耐甲氧西林金黄色葡萄球菌（MRSA）的先天免疫反应最终形成脓肿，以防止细菌传播和组织损伤。病原体识别受体（PRRs）决定了微生物控制和伤害之间的平衡。因此，细胞内的“刹车”对于调节适当的宿主防御和诱导解决至关重要。细胞内细胞因子信号传导1抑制因子（SOCS-1）是一种已知的JAK/STAT抑制剂，可阻止PRR接头和下游效应物的表达和作用。SOCS-1是否为皮肤宿主防御的分子成分仍有待确定。我们假设SOCS-1可以减少I型干扰素的产生和ifnar介导的抗菌效应功能，从而限制皮肤感染期间的炎症反应。我们的数据显示，MRSA皮肤感染增强了SOCS-1的表达，与用混乱肽对照处理的野生型小鼠相比，SOCS-1抑制剂肽处理和骨髓特异性SOCS-1缺陷小鼠的病变大小、细菌负荷和脓肿厚度都有所减少。SOCS-1缺失/抑制增加吞噬作用和细菌杀灭，依赖于一氧化氮的释放。SOCS-1抑制也会增加体内I型和II型干扰素水平。IFNAR缺失和抗体阻断在体内消除了SOCS-1抑制的有益作用。值得注意的是，我们发现高血糖会触发异常的SOCS-1表达，这与感染皮肤中总体IFN特征的降低有关。SOCS-1抑制可恢复高血糖易感小鼠的皮肤宿主防御。总的来说，这些数据证明了socs -1介导的I型干扰素在MRSA皮肤感染期间宿主防御和炎症中的作用。金黄色葡萄球菌皮肤和软组织感染的控制是由吞噬细胞和结构细胞的促炎和抗炎作用之间的平衡决定的。尽管大多数研究都集中在炎症介质的作用上，但细胞内效应物在皮肤感染过程中形成先天免疫反应的作用尚不清楚。在这里，我们确定了迄今为止未知的细胞内细胞因子信号传导免疫反应抑制因子1 （SOCS-1）负调节因子在金黄色葡萄球菌皮肤感染控制中的作用。骨髓特异性SOCS-1表达通过抑制I型干扰素（IFN）依赖性一氧化氮的产生和细菌杀伤，对皮肤感染有害。一种SOCS-1阻断肽可大大增强皮肤宿主的防御能力。重要的是，在高血糖模型中，我们将SOCS-1表达增加与宿主防御受损联系起来。转录组学分析显示，ifn相关基因的表达总体下降，遗传和药理学阻断SOCS-1恢复了高血糖小鼠的皮肤宿主防御。总之，我们的工作证明了先前未记载的对socs1依赖性皮肤宿主防御的有害作用，并表明阻断socs1 -1可能使宿主在稳态和高血糖条件下有效地控制感染。
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. 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.
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