Aberrant inflammation and lethality to septic peritonitis in mice lacking STAT3 in macrophages and neutrophils
Aberrant inflammation and lethality to septic peritonitis in mice lacking STAT3 in macrophages and neutrophils
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DOI：
10.4049/jimmunol.171.11.6198
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发表时间：
2003-12-01
影响因子：
4.4
通讯作者：
Akira, S
中科院分区：
文献类型：
--
作者：
Matsukawa, A;Takeda, K;Akira, S
Stat 3是介导IL-10抗炎特性的转录因子。在本研究中，我们证明了先天免疫细胞中表达的Stat 3在盲肠结扎穿孔（CLP）诱导的脓毒性腹膜炎中的关键作用。巨噬细胞和中性粒细胞中Stat 3靶向破坏的小鼠死于CLP诱导的脓毒性腹膜炎。相对于对照小鼠，小鼠表现出过度的局部和全身炎症，该事件伴随着多种细胞因子水平的显著增加。Stat 3缺乏小鼠肝、肾损伤明显加重。尽管炎症反应增强，但与对照小鼠相比，小鼠未能促进细菌清除。此外，在腹腔内接种从CLP小鼠中回收的活细菌后，小鼠表现出致死率增加。在体外，常驻腹腔巨噬细胞与Stat 3缺陷的小鼠受损的杀菌活性相对于控制，而炎症细胞因子的生产显着增强时，细胞刺激与合成脂肽，巨噬细胞活化脂肽-2和LPS。与Stat 3缺陷相比，Stat 3缺陷引起的巨噬细胞和中性粒细胞的杀菌活性也受损。溶酶体酶的释放，细菌清除的效应分子，显着减少与Stat 3缺陷引起的白细胞，同时增加炎症细胞因子的生产。总之，这些结果表明，巨噬细胞/嗜中性粒细胞特异性STAT 3不仅在调节与全身性炎症相关的多器官衰竭中至关重要，而且还增强了杀菌活性，这突出了细胞特异性Stat 3在脓毒症期间保护性免疫中的重要性。
Stat3 is a transcription factor mediating anti-inflammatory properties of IL-10. In the present study, we demonstrate a pivotal role of Stat3 expressed in innate immune cells during septic peritonitis induced by cecal ligation and puncture (CLP). Mice with targeted disruption of Stat3 in macrophages and neutrophils were succumbed to septic peritonitis induced by CLP. The mice displayed an excessive local and systemic inflammation relative to the control mice, an event that was accompanied by substantial increases in the level of multiple cytokines. Hepatic and renal injury was significantly exacerbated in mice with Stat3 deficiency. Despite enhanced inflammatory responses, the mice failed to facilitate bacterial clearance as compared with the control mice. In addition, the mice exhibited an increased lethality after i.p. inoculation of live bacteria recovered from CLP-mice. In vitro, resident peritoneal macrophages from mice with Stat3 deficiency impaired bactericidal activity relative to the control whereas productions of inflammatory cytokines were significantly augmented when cells were stimulated with a synthetic lipopeptide, macrophage-activating lipopeptide-2 and LPS. Elicited macrophages and neutrophils with Stat3 deficiency also impaired bactericidal activity as compared with those with Stat3. Lysosomal enzyme release, an effector molecule for bacterial clearance, was significantly decreased in elicited leukocytes with Stat3 deficiency while increasing the production of inflammatory cytokines. Altogether, these results suggest that macrophage/neutrophil-specific STAT3 is crucial in not only modulating multiple organ failure associated with systemic inflammation but also intensifying the bactericidal activity, which highlight the significance of cell-specific Stat3 in the protective immunity during sepsis.