Hollwedel Femke D, Maus Regina, Stolper Jennifer, Khan Ayesha, Stocker Bridget L, Timmer Mattie S M, Lu Xiuyuan, Pich Andreas, Welte Tobias, Yamasaki Sho, Maus Ulrich A
Division of Experimental Pneumology, Hannover Medical School, Hannover 30625, Germany.
School of Chemical and Physical Sciences, Victoria University of Wellington, Wellington 6140, New Zealand.
J Immunol. 2020 Dec 15;205(12):3390-3399. doi: 10.4049/jimmunol.2000509. Epub 2020 Nov 6.
Macrophage-inducible C-type lectin (Mincle)-dependent sensing of pathogens triggers proinflammatory immune responses in professional phagocytes that contribute to protecting the host against pathogen invasion. In this study, we examined whether overexpression of Mincle that is designed to improve early pathogen sensing by professional phagocytes would improve lung-protective immunity against in mice. Proteomic profiling of alveolar macrophages of Mincle transgenic (tg) mice stimulated with the Mincle-specific pneumococcal ligand glucosyl-diacylglycerol (Glc-DAG) revealed increased Nlrp3 inflammasome activation and downstream IL-1β cytokine release that was not observed in Glc-DAG-stimulated Mincle knockout or Nlrp3 knockout macrophages. Along this line, Mincle tg mice also responded with a stronger Nlrp3 expression and early proinflammatory cytokine release after challenge with , ultimately leading to fatal pneumonia in the Mincle tg mice. Importantly, Nlrp3 inhibitor treatment of Mincle tg mice significantly mitigated the observed hyperinflammatory response to pneumococcal challenge. Together, we show that overexpression of the pattern recognition receptor Mincle triggers increased Glc-DAG-dependent Nlrp3 inflammasome activation in professional phagocytes leading to fatal pneumococcal pneumonia in mice that is amenable to Nlrp3 inhibitor treatment. These data show that ectopic expression of the Mincle receptor confers increased susceptibility rather than resistance to in mice, thus highlighting the importance of an inducible Mincle receptor expression in response to microbial challenge.
巨噬细胞诱导性C型凝集素（Mincle）对病原体的感应可触发专业吞噬细胞中的促炎免疫反应，有助于保护宿主抵御病原体入侵。在本研究中，我们检测了旨在改善专业吞噬细胞早期病原体感应的Mincle过表达是否会增强小鼠对肺炎球菌的肺保护性免疫。用Mincle特异性肺炎球菌配体糖基二酰甘油（Glc-DAG）刺激Mincle转基因（tg）小鼠的肺泡巨噬细胞进行蛋白质组分析，结果显示Nlrp3炎性小体激活增加以及下游IL-1β细胞因子释放增加，而在Glc-DAG刺激的Mincle基因敲除或Nlrp3基因敲除巨噬细胞中未观察到这种情况。同样，Mincle tg小鼠在受到肺炎球菌攻击后也表现出更强的Nlrp3表达和早期促炎细胞因子释放，最终导致Mincle tg小鼠发生致命性肺炎。重要的是，用Nlrp3抑制剂治疗Mincle tg小鼠可显著减轻观察到的对肺炎球菌攻击的过度炎症反应。我们共同表明，模式识别受体Mincle的过表达会触发专业吞噬细胞中Glc-DAG依赖性Nlrp3炎性小体激活增加，导致小鼠发生致命性肺炎球菌肺炎，而Nlrp3抑制剂治疗对此有效。这些数据表明，Mincle受体的异位表达使小鼠对肺炎球菌的易感性增加而非抵抗力增强，从而突出了诱导性Mincle受体表达对微生物攻击作出反应的重要性。
