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。
Dectin-1 aggravates neutrophil inflammation through caspase-11/4-mediated macrophage pyroptosis in asthma.
机构信息
Department of Respiratory Medicine, National Key Clinical Specialty, Branch of National Clinical Research Center for Respiratory Disease, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
出版信息
Respir Res. 2024 Mar 8;25(1):119. doi: 10.1186/s12931-024-02743-z.
BACKGROUND
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.
METHODS
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.
RESULTS
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.
CONCLUSION
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.
背景
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 已被证明可促进焦亡，这是严重哮喘气道炎症的标志。然而，非经典焦亡信号 caspase-11/4 及其上游调节机制在哮喘中的作用尚未完全探索。
方法
用 Dectin-1 激动剂几丁质和 Dectin-1 抑制剂昆布多糖以及 caspase-11 抑制剂 Wedelolactone 分别处理屋尘螨（HDM）诱导的小鼠。然后分析支气管肺泡灌洗液（BALF）中的炎性细胞。通过 Western blot 测定 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、焦亡因子与中性粒细胞的相关性。
结果
几丁质似乎加重了哮喘小鼠的中性粒细胞气道炎症，而 Wedelolactone 则有效缓解了几丁质加重的气道炎症。此外，几丁质增强了 HDM 刺激体内或体外 caspase-11 激活片段和 gasdermin D（GSDMD-N）的 N 端片段的释放。在鼠肺泡巨噬细胞（MH-S 细胞）中，几丁质/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 的表达上调，这一过程被 Wedelolactone 抑制。在哮喘患者中，巨噬细胞上 Dectin-1 的表达与 caspase-4（caspase-11 的人类同源物）以及诱导痰中中性粒细胞的比例呈正相关。
结论
哮喘中 Dectin-1 的激活激活了 caspase-11/4 介导的巨噬细胞焦亡，进而刺激趋化因子的分泌，导致气道中性粒细胞炎症的加重。
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