The pattern recognition receptor Dectin-1 was initially discovered to play a pivotal role in mediating pulmonary antifungal immunity and promoting neutrophil-driven inflammation. Recent studies have revealed that Dectin-1 is overexpressed in asthma, but the specific mechanism remains elusive. Additionally, Dectin-1 has been implicated in promoting pyroptosis, a hallmark of severe asthma airway inflammation. Nevertheless, the involvement of the non-classical pyroptosis signal caspase-11/4 and its upstream regulatory mechanisms in asthma has not been completely explored. House dust mite (HDM)-induced mice was treated with Dectin-1 agonist Curdlan, Dectin-1 inhibitor Laminarin, and caspase-11 inhibitor wedelolactone separately. Subsequently, inflammatory cells in bronchoalveolar lavage fluid (BALF) were analyzed. Western blotting was performed to measure the protein expression of caspase-11 and gasdermin D (GSDMD). Cell pyroptosis and the expression of chemokine were detected in vitro. The correlation between Dectin-1 expression, pyroptosis factors and neutrophils in the induced sputum of asthma patients was analyzed. Curdlan appeared to exacerbate neutrophil airway inflammation in asthmatic mice, whereas wedelolactone effectively alleviated airway inflammation aggravated by Curdlan. Moreover, Curdlan enhanced the release of caspase-11 activation fragments and N-terminal fragments of gasdermin D (GSDMD-N) stimulated by HDM both in vivo or in vitro. In mouse alveolar macrophages (MH-S cells), Curdlan/HDM stimulation resulted in vacuolar degeneration and elevated lactate dehydrogenase (LDH) release. In addition, there was an upregulation of neutrophil chemokines CXCL1, CXCL3, CXCL5 and their receptor CXCR2, which was suppressed by wedelolactone. In asthma patients, a positive correlation was observed between the expression of Dectin-1 on macrophages and caspase-4 (the human homology of caspase-11), and the proportion of neutrophils in induced sputum. Dectin-1 activation in asthma induced caspase-11/4 mediated macrophage pyroptosis, which subsequently stimulated the secretion of chemokines, leading to the exacerbation of airway neutrophil inflammation.

中文翻译：

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Dectin-1 通过 caspase-11/4 介导的巨噬细胞焦亡加重哮喘中的中性粒细胞炎症

模式识别受体 Dectin-1 最初被发现在介导肺部抗真菌免疫和促进中性粒细胞驱动的炎症中发挥关键作用。最近的研究表明Dectin-1在哮喘中过度表达，但具体机制仍不清楚。此外，Dectin-1 与促进细胞焦亡有关，这是严重哮喘气道炎症的一个标志。然而，非经典细胞焦亡信号caspase-11/4及其上游调节机制在哮喘中的作用尚未得到完全探索。分别用 Dectin-1 激动剂 Curdlan、Dectin-1 抑制剂昆布多糖和 caspase-11 抑制剂蟛蜞菊内酯治疗屋尘螨 (HDM) 诱导的小鼠。随后，分析了支气管肺泡灌洗液（BALF）中的炎症细胞。采用蛋白质印迹法检测 caspase-11 和gasdermin D (GSDMD) 的蛋白表达。体外检测细胞焦亡和趋化因子的表达。分析哮喘患者诱导痰中Dectin-1表达量、细胞焦亡因子及中性粒细胞的相关性。Curdlan 似乎加剧了哮喘小鼠的中性粒细胞气道炎症，而蟛蜞菊内酯则有效缓解了 Curdlan 加剧的气道炎症。此外，Curdlan 增强了 HDM 体内或体外刺激的 caspase-11 激活片段和 Gasdermin D N 末端片段 (GSDMD-N) 的释放。在小鼠肺泡巨噬细胞（MH-S 细胞）中，Curdlan/HDM 刺激导致空泡变性和乳酸脱氢酶 (LDH) 释放增加。此外，中性粒细胞趋化因子 CXCL1、CXCL3、CXCL5 及其受体 CXCR2 上调，但可被蟛蜞菊内酯抑制。在哮喘患者中，巨噬细胞上Dectin-1和caspase-4（caspase-11的人类同源物）的表达与诱导痰中中性粒细胞的比例呈正相关。哮喘中 Dectin-1 的激活诱导 caspase-11/4 介导的巨噬细胞焦亡，随后刺激趋化因子的分泌，导致气道中性粒细胞炎症加剧。