Department of Thoracic Surgery, The First Affiliated Hospital of Nanjing Medical University, 210029 Nanjing, Jiangsu, China.
Institute of Molecular Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 200127 Shanghai, China.
Front Biosci (Landmark Ed). 2024 Nov 21;29(11):397. doi: 10.31083/j.fbl2911397.
Infection is the leading cause of acute lung injury (ALI). Macrophages, which are pivotal innate immune cells, play a critical role in mediating inflammatory processes. Intracellular lipopolysaccharide (LPS) from invasive Gram-negative bacteria can activate the caspase-11 inflammasome, leading to the induction of pyroptosis in macrophages. This process subsequently triggers the release of inflammatory cytokines and damage-associated molecular patterns from pyroptotic macrophages, thereby exacerbating inflammatory progression in ALI. However, the precise regulatory mechanisms governing caspase-11 activation is still unclear. Sentrin-specific proteases (SENPs) have been identified as notable targets for their anti-inflammatory properties. Nevertheless, the specific role of SENPs in macrophage pyroptosis during the pathogenesis of ALI remains unknown.
We used LPS as an endotoxin to induce ALI. We analyzed the expression and location of sentrin-specific protease 1 (SENP1), pulmonary impairment, macrophage infiltration, caspase-11 inflammasome expression and activation, caspase-11 SUMOylation, and inflammatory cytokine secretion.
Upregulated expression of SENP1 in lung tissue and macrophages was observed following LPS stimulation. SENP1 mediates de-SUMOylation and activation of caspase-11 inflammasome in macrophages. Moreover, pharmacological inhibition or genetic deficiency of SENP1 in macrophages significantly improved ALI-related histological damage by reducing the secretion of inflammatory cytokines and suppressing caspase-11-dependent pyroptosis.
Collectively, our findings highlight the involvement of SENP1 in caspase-11 activation and inflammatory progression in macrophages, thereby establishing a scientific foundation for the exploration of novel therapeutic strategies aimed at treating ALI.
感染是急性肺损伤（ALI）的主要原因。巨噬细胞作为关键的先天免疫细胞，在介导炎症过程中起着至关重要的作用。来自侵袭性革兰氏阴性菌的细胞内脂多糖（LPS）可以激活半胱天冬酶-11 炎性小体，导致巨噬细胞发生细胞焦亡。这一过程随后会触发炎性细胞因子和损伤相关分子模式从焦亡的巨噬细胞中释放，从而加剧 ALI 中的炎症进展。然而，调控半胱天冬酶-11 激活的确切机制仍不清楚。 泛素特异性蛋白酶（SENPs）已被确定为具有抗炎特性的重要靶点。然而，SENPs 在 ALI 发病机制中巨噬细胞细胞焦亡中的具体作用尚不清楚。
我们使用 LPS 作为内毒素诱导 ALI。我们分析了泛素特异性蛋白酶 1（SENP1）的表达和定位、肺损伤、巨噬细胞浸润、半胱天冬酶-11 炎性小体的表达和激活、半胱天冬酶-11 SUMO 化以及炎性细胞因子的分泌。
在 LPS 刺激后，肺组织和巨噬细胞中 SENP1 的表达上调。SENP1 介导巨噬细胞中半胱天冬酶-11 炎性小体的去 SUMO 化和激活。此外，在巨噬细胞中，SENP1 的药理学抑制或基因缺失通过减少炎性细胞因子的分泌和抑制半胱天冬酶-11 依赖性细胞焦亡，显著改善了与 ALI 相关的组织学损伤。
综上所述，我们的研究结果表明 SENP1 参与了巨噬细胞中半胱天冬酶-11 的激活和炎症进展，为探索治疗 ALI 的新治疗策略奠定了科学基础。
