BATF2 enhances proinflammatory cytokine responses in macrophages and improves early host defense against pulmonary Klebsiella pneumoniae infection.
BATF2 enhances proinflammatory cytokine responses in macrophages and improves early host defense against pulmonary Klebsiella pneumoniae infection.
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BATF2 增强巨噬细胞中的促炎细胞因子反应，并改善宿主对肺部肺炎克雷伯菌感染的早期防御。
DOI：
10.1152/ajplung.00441.2022
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Lee,JanetS
中科院分区：
文献类型：
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作者：
vanderGeest,Rick;Peñaloza,HernánF;Xiong,Zeyu;Gonzalez-Ferrer,Shekina;An,Xiaojing;Li,Huihua;Fan,Hongye;Tabary,Mohammadreza;Nouraie,SMehdi;Zhao,Yanwu;Zhang,Yingze;Chen,Kong;Alder,JonathanK;Bain,WilliamG;Lee,JanetS
碱性亮氨酸拉链转录因子ATF样2（BATF 2）是一种转录因子，正在成为先天免疫系统的重要调节因子。BATF 2是LPS处理的人肺泡巨噬细胞中上调最多的基因之一，但诱导BATF 2表达以响应革兰氏阴性刺激的信号传导途径尚不完全清楚。此外，BATF 2在宿主对革兰氏阴性病原体如肺炎克雷伯氏菌（Kp）肺部感染应答中的作用尚不清楚。我们发现，诱导Batf 2基因表达的巨噬细胞在体外响应Kpin需要TRIF和I型干扰素（IFN）信号，但不是MyD 88信号。BATF 2缺陷对体外巨噬细胞效应功能的影响的分析表明，BATF 2不直接影响巨噬细胞吞噬摄取和Kp的细胞内杀伤。然而，BATF 2显著增强巨噬细胞促炎基因表达和Kp诱导的细胞因子反应。在体内，与野生型（WT）小鼠相比，肺Kp感染后24 h，野生型（WT）小鼠肺组织中Batf 2基因表达升高，Kp感染的BATF 2缺陷型（Batf 2 −/−）小鼠肺、脾和肝脏中的细菌负荷增加。WT和Batf 2 −/−小鼠在感染后表现出类似的白细胞募集，但与体外观察结果一致，Batf 2 −/−小鼠肺泡腔内的促炎细胞因子水平降低。总之，这些结果表明，BATF 2增强了巨噬细胞中的促炎细胞因子反应，以响应Kp，并有助于早期宿主防御pulmonaryKp infection.NEW & NOTEWORTHThis研究调查了介导诱导TLR 4下游的BATF 2表达的信号通路，以及BATF 2对宿主防御pulmonaryKp infection的影响。我们证明Kp诱导的巨噬细胞中BATF 2的上调需要TRIF和I型IFN信号。我们还发现，BATF 2增强了Kp诱导的巨噬细胞细胞因子反应，并且BATF 2有助于宿主对肺Kp感染的早期防御。
Basic leucine zipper transcription factor ATF-like 2 (BATF2) is a transcription factor that is emerging as an important regulator of the innate immune system. BATF2 is among the top upregulated genes in human alveolar macrophages treated with LPS, but the signaling pathways that induce BATF2 expression in response to Gram-negative stimuli are incompletely understood. In addition, the role of BATF2 in the host response to pulmonary infection with a Gram-negative pathogen likeKlebsiella pneumoniae(Kp) is not known. We show that induction ofBatf2gene expression in macrophages in response toKpin vitro requires TRIF and type I interferon (IFN) signaling, but not MyD88 signaling. Analysis of the impact of BATF2 deficiency on macrophage effector functions in vitro showed that BATF2 does not directly impact macrophage phagocytic uptake and intracellular killing ofKp. However, BATF2 markedly enhanced macrophage proinflammatory gene expression andKp-induced cytokine responses. In vivo,Batf2gene expression was elevated in lung tissue of wild-type (WT) mice 24 h after pulmonaryKpinfection, andKp-infected BATF2-deficient (Batf2−/−) mice displayed an increase in bacterial burden in the lung, spleen, and liver compared with WT mice. WT andBatf2−/−mice showed similar recruitment of leukocytes following infection, but in line with in vitro observations, proinflammatory cytokine levels in the alveolar space were reduced inBatf2−/−mice. Altogether, these results suggest that BATF2 enhances proinflammatory cytokine responses in macrophages in response toKpand contributes to the early host defense against pulmonaryKpinfection.NEW & NOTEWORTHYThis study investigates the signaling pathways that mediate induction of BATF2 expression downstream of TLR4 and also the impact of BATF2 on the host defense against pulmonaryKpinfection. We demonstrate thatKp-induced upregulation of BATF2 in macrophages requires TRIF and type I IFN signaling. We also show that BATF2 enhancesKp-induced macrophage cytokine responses and that BATF2 contributes to the early host defense against pulmonaryKpinfection.