吞噬细胞死亡导致家族性地中海热中促炎性 S100A12 的释放增强

IF 2.4 Q1 PEDIATRICS Molecular and cellular pediatrics Pub Date : 2023-12-13 DOI:10.1186/s40348-023-00173-3
G. Varga, S. Schleifenbaum, U. Koenig, J. Waldkirch, C. Hinze, C. Kessel, W. Geluk, T. Pap, Elke Lainka, Tilmann Kallinich, D. Foell, H. Wittkowski
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引用次数: 0

摘要

家族性地中海热(FMF)是一种与吞噬细胞活化有关的典型自身炎症综合征。单核细胞、粒细胞、树突状细胞和滑膜成纤维细胞中都有 Pyrin 的表达。Pyrin 的功能是细胞膜模式识别受体,并形成一个独特的 pyrin 炎性体。吞噬细胞特异性蛋白 S100A12 主要在粒细胞中表达,属于损伤相关分子模式(DAMP)。在 FMF 患者的血清中可以检测到 S100A12 的大量升高,即使在临床上疾病并不活跃的情况下也是如此。因此,我们研究了临床表现不活跃的 FMF 患者粒细胞释放 S100A12 的机制。我们证明,临床非活动期患者的 FMF 中性粒细胞具有导致细胞死亡的内在活性,即使在外源性未刺激的中性粒细胞中也是如此。细胞死亡类似于NETosis,依赖于ROS和孔形成蛋白gasdermin D(GSDMD),因为两者的抑制剂都能完全阻止细胞死亡和S100A12的释放。当使用梭状芽孢杆菌毒素 A(pyrin-activator TcdA)进行刺激时,与 HC 中性粒细胞相比,FMF 患者中性粒细胞的中性粒细胞死亡和 S100A12 释放明显增强。我们能够证明,非活动性 FMF 患者中性粒细胞的活化阈值降低了,这很可能是由于预先激活了 pyrin。在体外培养时,FMF 嗜中性粒细胞会产生更多的 ROS。这种较高的基线 ROS 活性导致 GSDMD 裂解增加,随后释放出 S100A12 等物质,并导致细胞死亡增加,表现出 NETosis 和 pyroptosis 的特征。我们首次发现,非活动性 FMF 患者中性粒细胞的细胞死亡途径很容易被触发,并导致 ROS 和 GSDMD 依赖性激活机制,甚至可能导致病理变化。这可以通过阻断 ROS 或 GSDMD 的裂解来解决,从而在高度活跃时减少炎症爆发。
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Phagocytic cell death leads to enhanced release of pro-inflammatory S100A12 in familial Mediterranean fever
Familial Mediterranean fever (FMF) is a prototypical autoinflammatory syndrome associated with phagocytic cell activation. Pyrin mutations are the genetic basis of this disease, and its expression has been shown in monocytes, granulocytes, dendritic cells, and synovial fibroblasts. Pyrin functions as a cytosolic pattern recognition receptor and forms a distinct pyrin inflammasome. The phagocyte-specific protein S100A12 is predominantly expressed in granulocytes and belongs to the group of damage associated molecular patterns (DAMP). S100A12 can be detected at massively elevated levels in the serum of FMF patients, even in clinically inactive disease. Whether this is crucial for FMF pathogenesis is as yet unknown, and we therefore investigated the mechanisms of S100A12 release from granulocytes of FMF patients presenting clinically inactive. We demonstrate that FMF neutrophils from patients in clinical inactive disease possess an intrinsic activity leading to cell death even in exogenously unstimulated neutrophils. Cell death resembles NETosis and is dependent on ROS and pore forming protein gasdermin D (GSDMD), as inhibitors for both are capable of completely block cell death and S100A12 release. When pyrin-activator TcdA (Clostridium difficile toxin A) is used to stimulate, neutrophilic cell death and S100A12 release are significantly enhanced in neutrophils from FMF patients compared to neutrophils from HC. We are able to demonstrate that activation threshold of neutrophils from inactive FMF patients is decreased, most likely by pre-activated pyrin. FMF neutrophils present with intrinsically higher ROS production, when cultured ex vivo. This higher baseline ROS activity leads to increased GSDMD cleavage and subsequent release of, e.g., S100A12, and to increased cell death with features of NETosis and pyroptosis. We show for the first time that cell death pathways in neutrophils of inactive FMF patients are easily triggered and lead to ROS- and GSDMD-dependent activation mechanisms and possibly pathology. This could be therapeutically addressed by blocking ROS or GSDMD cleavage to decrease inflammatory outbreaks when becoming highly active.
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