The circadian clock regulates many aspects of immunity. Bacterial infections are affected by time of day, but the mechanisms involved remain undefined. Here we show that loss of the core clock protein BMAL1 in macrophages confers protection against pneumococcal pneumonia. Infected mice show both reduced weight loss and lower bacterial burden in circulating blood. In vivo studies of macrophage phagocytosis reveal increased bacterial ingestion following Bmal1 deletion, which was also seen in vitro. BMAL1-/- macrophages exhibited marked differences in actin cytoskeletal organization, a phosphoproteome enriched for cytoskeletal changes, with reduced phosphocofilin and increased active RhoA. Further analysis of the BMAL1-/- macrophages identified altered cell morphology and increased motility. Mechanistically, BMAL1 regulated a network of cell movement genes, 148 of which were within 100 kb of high-confidence BMAL1 binding sites. Links to RhoA function were identified, with 29 genes impacting RhoA expression or activation. RhoA inhibition restored the phagocytic phenotype to that seen in control macrophages. In summary, we identify a surprising gain of antibacterial function due to loss of BMAL1 in macrophages, associated with a RhoA-dependent cytoskeletal change, an increase in cell motility, and gain of phagocytic function.

中文翻译：

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时钟基因 Bmal1 抑制巨噬细胞运动、吞噬作用，并削弱对肺炎的防御能力。

生物钟调节免疫力的许多方面。细菌感染受一天中时间的影响，但所涉及的机制仍未明确。在这里，我们表明巨噬细胞中核心时钟蛋白 BMAL1 的缺失赋予了针对肺炎球菌肺炎的保护作用。受感染的小鼠体重减轻减少，循环血液中的细菌负荷也降低。巨噬细胞吞噬作用的体内研究表明，Bmal1 缺失后细菌摄入增加，这在体外也有观察到。BMAL1-/- 巨噬细胞在肌动蛋白细胞骨架组织中表现出显着差异，这是一种富含细胞骨架变化的磷酸化蛋白质组，具有减少的磷酸肌动蛋白和增加的活性 RhoA。对 BMAL1-/- 巨噬细胞的进一步分析确定了细胞形态的改变和运动性的增加。从机械上讲，BMAL1 调节细胞运动基因网络，其中 148 个位于高置信度 BMAL1 结合位点的 100 kb 以内。确定了与 RhoA 功能的联系，其中有 29 个基因影响 RhoA 的表达或激活。RhoA 抑制将吞噬表型恢复到对照巨噬细胞中所见的表型。总之，我们发现由于巨噬细胞中 BMAL1 的缺失导致抗菌功能的惊人增加，与 RhoA 依赖性细胞骨架变化、细胞运动增加和吞噬功能增加相关。