Key Points IRF3 contributes to sepsis in a mouse model incorporating antibiotics and fluids. IRF3 acts in stromal cells (nonleukocytes) to mediate this effect. IRF3 indirectly alters macrophage behavior and the inflammatory network in sepsis. Visual Abstract IFN regulatory factor 3 (IRF3) is a transcription factor that is activated by multiple pattern-recognition receptors. We demonstrated previously that IRF3 plays a detrimental role in a severe mouse model of sepsis, induced by cecal ligation and puncture. In this study, we found that IRF3–knockout (KO) mice were greatly protected from sepsis in a clinically relevant version of the cecal ligation and puncture model incorporating crystalloid fluids and antibiotics, exhibiting improved survival, reduced disease score, lower levels of serum cytokines, and improved phagocytic function relative to wild-type (WT) mice. Computational modeling revealed that the overall complexity of the systemic inflammatory/immune network was similar in IRF3-KO versus WT septic mice, although the tempo of connectivity differed. Furthermore, the mediators driving the network differed: TNF-α, IL-1β, and IL-6 predominated in WT mice, whereas MCP-1 and IL-6 predominated in IRF3-KO mice. Network analysis also suggested differential IL-6–related inflammatory programs in WT versus IRF3-KO mice. We created bone marrow chimeras to test the role of IRF3 within leukocytes versus stroma. Surprisingly, chimeras with IRF3-KO bone marrow showed little protection from sepsis, whereas chimeras with IRF3-KO stroma showed a substantial degree of protection. We found that WT and IRF3-KO macrophages had a similar capacity to produce IL-6 and phagocytose bacteria in vitro. Adoptive transfer experiments demonstrated that the genotype of the host environment affected the capacity of monocytes to produce IL-6 during sepsis. Thus, IRF3 acts principally within the stromal compartment to exacerbate sepsis pathogenesis via differential impacts on IL-6–related inflammatory programs.

中文翻译：

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小鼠基质内的 IRF3 信号传导影响脓毒症发病机制

关键点 IRF3 有助于结合抗生素和液体的小鼠模型中的败血症。IRF3 在基质细胞（非白细胞）中起作用以介导这种作用。IRF3 间接改变败血症中的巨噬细胞行为和炎症网络。Visual Abstract IFN 调节因子 3 (IRF3) 是一种转录因子，可被多种模式识别受体激活。我们之前证明 IRF3 在由盲肠结扎和穿刺诱导的严重败血症小鼠模型中起有害作用。在这项研究中，我们发现 IRF3 基因敲除 (KO) 小鼠在结合晶体液和抗生素的盲肠结扎和穿刺模型的临床相关版本中得到了极大的预防败血症，表现出存活率提高、疾病评分降低、血清细胞因子水平降低, 并且相对于野生型（WT）小鼠改善了吞噬功能。计算模型显示，IRF3-KO 与 WT 脓毒症小鼠的全身炎症/免疫网络的总体复杂性相似，尽管连接速度不同。此外，驱动网络的介质不同：TNF-α、IL-1β 和 IL-6 在 WT 小鼠中占主导地位，而 MCP-1 和 IL-6 在 IRF3-KO 小鼠中占主导地位。网络分析还表明 WT 与 IRF3-KO 小鼠中不同的 IL-6 相关炎症程序。我们创建了骨髓嵌合体来测试 IRF3 在白细胞与基质中的作用。令人惊讶的是，具有 IRF3-KO 骨髓的嵌合体几乎没有显示出对败血症的保护作用，而具有 IRF3-KO 基质的嵌合体显示出相当程度的保护作用。我们发现 WT 和 IRF3-KO 巨噬细胞在体外产生 IL-6 和吞噬细菌的能力相似。过继转移实验表明，宿主环境的基因型影响脓毒症期间单核细胞产生 IL-6 的能力。因此，IRF3 主要在基质隔室内起作用，通过对 IL-6 相关炎症程序的不同影响来加剧脓毒症发病机制。