Abstract：
Sepsis is a widespread and life-threatening disease characterised by infection-triggered immune hyperactivation and cytokine storms, culminating in tissue damage and multiple organ dysfunction syndrome. BMAL1 is a pivotal transcription factor in the circadian clock that plays a crucial role in maintaining immune homeostasis. BMAL1 dysregulation has been implicated in inflammatory diseases and immunodeficiency. However, the mechanisms underlying BMAL1 disruption in sepsis-induced acute lung injury (ALI) remain poorly understood. In vitro, we used THP1 and mouse peritoneal macrophages to elucidate the potential mechanism of BMAL1 function in sepsis. In vivo, an endotoxemia model was used to investigate the effect of BMAL1 on sepsis and the therapeutic role of targeting CXCR2. We showed that BMAL1 significantly affected the regulation of innate immunity in sepsis-induced ALI. BMAL1 deficiency in the macrophages exacerbated systemic inflammation and sepsis-induced ALI. Mechanistically, BMAL1 acted as a transcriptional suppressor and regulated the expression of CXCL2. BMAL1 deficiency in macrophages upregulated CXCL2 expression, increasing the recruitment of polymorphonuclear neutrophils and the formation of neutrophil extracellular traps (NETs) by binding to the chemokine receptor CXCR2, thereby intensifying lung injury in a sepsis model. Furthermore, a selective inhibitor of CXCR2, SB225002, exerted promising therapeutic effects by markedly reducing neutrophil infiltration and NETs formation and alleviating lung injury. Importantly, CXCR2 blockade mitigated multiple organ dysfunction. Collectively, these findings suggest that BMAL1 controls the CXCL2/CXCR2 pathway, and the therapeutic efficacy of targeting CXCR2 in sepsis has been validated, presenting BMAL1 as a potential therapeutic target for lethal infections.
摘要：
脓毒症是一种广泛且危及生命的疾病，其特征是感染引发的免疫过度激活和细胞因子风暴。最终导致组织损伤和多器官功能障碍综合征。BMAL1是昼夜节律中的关键转录因子，在维持免疫稳态中起着至关重要的作用。BMAL1失调与炎性疾病和免疫缺陷有关。然而,在脓毒症诱导的急性肺损伤(ALI)中BMAL1破坏的潜在机制仍知之甚少.体外，我们使用THP1和小鼠腹腔巨噬细胞来阐明BMAL1在脓毒症中的潜在作用机制.在体内,使用内毒素血症模型研究BMAL1对脓毒症的影响以及靶向CXCR2的治疗作用.我们表明BMAL1显著影响脓毒症诱导的ALI的先天免疫的调节。巨噬细胞中的BMAL1缺乏加剧了全身性炎症和脓毒症诱导的ALI。机械上,BMAL1作为转录抑制因子，调节CXCL2的表达。巨噬细胞中的BMAL1缺乏上调CXCL2表达，通过与趋化因子受体CXCR2结合，增加多形核中性粒细胞的募集和中性粒细胞胞外陷阱（NETs）的形成，从而加剧脓毒症模型中的肺损伤。此外，CXCR2的选择性抑制剂SB225002通过显着减少中性粒细胞浸润和NETs形成并减轻肺损伤而发挥了有希望的治疗作用。重要的是,CXCR2阻断减轻多器官功能障碍。总的来说，这些发现表明BMAL1控制CXCL2/CXCR2通路，靶向CXCR2在脓毒症中的治疗效果已经得到验证，BMAL1是致死性感染的潜在治疗靶点。
