Varga G, Schleifenbaum S, Koenig U, Waldkirch J, Hinze C, Kessel C, Geluk W, Pap T, Lainka Elke, Kallinich Tilmann, Foell D, Wittkowski H
Department of Pediatric Rheumatology and Immunology, University Children's Hospital Muenster, Muenster, Germany.
Institute of Musculoskeletal Medicine (IMM), University Hospital Muenster, Muenster, Germany.
Mol Cell Pediatr. 2023 Dec 13;10(1):19. doi: 10.1186/s40348-023-00173-3.
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.
家族性地中海热（FMF）是一种与吞噬细胞活化相关的典型自身炎症综合征。 吡啉突变是该疾病的遗传基础，并且已在单核细胞、粒细胞、树突状细胞和滑膜成纤维细胞中显示其表达。 吡啉作为一种胞质模式识别受体，形成独特的吡啉炎性小体。 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）组。 即使在临床非活动期疾病中，也可以在FMF患者的血清中检测到大量升高水平的S100A12。 这是否对FMF发病机制至关重要尚不清楚，因此我们研究了临床非活动期FMF患者粒细胞释放S100A12的机制。
我们证明，临床非活动期疾病患者的FMF中性粒细胞具有内在活性，即使在外源未刺激的中性粒细胞中也会导致细胞死亡。 细胞死亡类似于中性粒细胞胞外诱捕网形成（NETosis），并且依赖于活性氧（ROS）和孔形成蛋白gasdermin D（GSDMD），因为两者的抑制剂都能够完全阻断细胞死亡和S100A12释放。 当使用吡啉激活剂TcdA（艰难梭菌毒素A）进行刺激时，与健康对照（HC）的中性粒细胞相比，FMF患者的中性粒细胞中的嗜中性细胞死亡和S100A12释放显著增强。
我们能够证明，非活动期FMF患者的中性粒细胞的激活阈值降低，最有可能是由于预先激活的吡啉。 当在体外培养时，FMF中性粒细胞具有内在更高的ROS产生。 这种更高的基线ROS活性导致GSDMD裂解增加以及随后例如S100A12的释放增加，并导致具有NETosis和细胞焦亡特征的细胞死亡增加。 我们首次表明，非活动期FMF患者的中性粒细胞中的细胞死亡途径很容易被触发，并导致ROS和GSDMD依赖性激活机制以及可能的病理状态。 当变得高度活跃时，这可以通过阻断ROS或GSDMD裂解来减少炎症爆发从而进行治疗。
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