Circadian disruption in lung fibroblasts enhances NF-κB activity to exacerbate neutrophil recruitment.
Circadian disruption in lung fibroblasts enhances NF-κB activity to exacerbate neutrophil recruitment.
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DOI：
10.1096/fj.202201456r
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发表时间：
2023-02
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成纤维细胞是在包括肺在内的整个组织中丰富的基质细胞。成纤维细胞是通过趋化因子分泌的免疫细胞募集的整体协调者。昼夜节律将免疫细胞的募集引导到肺部，这反过来又影响对感染和存活的反应。虽然成纤维细胞显示出强大的昼夜节律，但成纤维细胞分子钟对免疫细胞肺特异性迁移和募集的贡献仍有待确定。黄昏时用脂多糖（LPS）鼻内激发的小鼠显示肺中促炎细胞因子IL-1β和趋化因子CXCL 5的表达增加，同时伴有中性粒细胞募集增加。敲低核心时钟基因Bmal 1的原代肺成纤维细胞和永生化Bmal 1 −/−肺成纤维细胞在IL-1β刺激下也显示出Cxcl 5表达增加。与Bmal 1 +/+肺成纤维细胞对照相比，从IL-1β刺激的Bmal 1 −/−永生化成纤维细胞获得的条件培养基诱导了更大的中性粒细胞迁移。在IL-1β刺激的Bmal 1 −/−肺成纤维细胞中，NF-κB亚基p65的磷酸化增强，NF-κB的药理学抑制减弱了在这些细胞中观察到的CXCL 5产生和中性粒细胞募集的增强。总的来说，这些结果表明Bmal 1抑制肺成纤维细胞中的NF-κB活性，以控制炎症反应期间趋化因子表达和免疫细胞募集。
Fibroblasts are stromal cells abundant throughout tissues, including the lungs. Fibroblasts are integral coordinators of immune cell recruitment through chemokine secretion. Circadian rhythms direct the recruitment of immune cells to the lung, which in turn impacts response to infection and survival. Although fibroblasts display robust circadian rhythms, the contribution of the fibroblast molecular clock to lung‐specific migration of immune cells and recruitment remains to be established. Mice challenged intranasally with lipopolysaccharide (LPS) at dusk showed increased expression of the pro‐inflammatory cytokine IL‐1β and chemokine CXCL5 in the lung, which was accompanied by increased neutrophil recruitment. Primary lung fibroblasts with knockdown of the core clock gene Bmal1 and immortalized Bmal1 −/− lung fibroblasts also displayed increased Cxcl5 expression under IL‐1β stimulation. Conditioned media obtained from IL‐1β‐stimulated Bmal1 −/− immortalized fibroblasts‐induced greater neutrophil migration compared with Bmal1 +/+ lung fibroblast controls. Phosphorylation of the NF‐κB subunit, p65, was enhanced in IL‐1β‐stimulated Bmal1 −/− lung fibroblasts, and pharmacological inhibition of NF‐κB attenuated the enhanced CXCL5 production and neutrophil recruitment observed in these cells. Collectively, these results demonstrate that Bmal1 represses NF‐κB activity in lung fibroblasts to control chemokine expression and immune cell recruitment during an inflammatory response.