德国心血管生理和病理生理研究所Markus Sperandio小组探明，E-选择素介导的NLRP3炎症小体快速激活通过瞬时gasdermin蛋白D孔形成调节中性粒细胞释放S100A8/S100A9。该项研究成果发表在2023年10月30日出版的《自然—免疫学》上。

他们发现在炎症期间，E-选择素诱导的S100A8/S100A9的快速释放以NLRP3炎症小体依赖的方式发生。从机制上讲，E-选择素的参与触发了布鲁顿酪氨酸激酶依赖的NLRP3酪氨酸磷酸化。伴随钾外排通过电压门控钾通道KV1.3介导ASC寡聚化。随后是caspase 1的裂解和下游成孔gasdermin蛋白D的激活，使S100A8/S100A9在胞质内释放。

引人注目的是，E-选择素介导的gasdermin蛋白D孔形成不会导致细胞死亡，而是一个涉及ESCRT III膜修复机制激活的短暂过程。这些数据阐明了受控制的S100A8/S100A9从中性粒细胞释放的分子机制，并确定了NLRP3/gasdermin D轴是炎症期间中性粒细胞快速可逆的激活系统。

据了解，S100A8/S100A9是骨髓细胞在许多急慢性炎症疾病中释放的促炎介质。然而，其从中性粒细胞胞质室释放的确切机制尚不清楚。

附：英文原文

Title: E-selectin-mediated rapid NLRP3 inflammasome activation regulates S100A8/S100A9 release from neutrophils via transient gasdermin D pore formation

Author: Pruenster, Monika, Immler, Roland, Roth, Jonas, Kuchler, Tim, Bromberger, Thomas, Napoli, Matteo, Nussbaumer, Katrin, Rohwedder, Ina, Wackerbarth, Lou Martha, Piantoni, Chiara, Hennis, Konstantin, Fink, Diana, Kallabis, Sebastian, Schroll, Tobias, Masgrau-Alsina, Sergi, Budke, Agnes, Liu, Wang, Vestweber, Dietmar, Wahl-Schott, Christian, Roth, Johannes, Meissner, Felix, Moser, Markus, Vogl, Thomas, Hornung, Veit, Broz, Petr, Sperandio, Markus

Issue&Volume: 2023-10-30

Abstract: S100A8/S100A9 is a proinflammatory mediator released by myeloid cells during many acute and chronic inflammatory disorders. However, the precise mechanism of its release from the cytosolic compartment of neutrophils is unclear. Here, we show that E-selectin-induced rapid S100A8/S100A9 release during inflammation occurs in an NLRP3 inflammasome-dependent fashion. Mechanistically, E-selectin engagement triggers Bruton’s tyrosine kinase-dependent tyrosine phosphorylation of NLRP3. Concomitant potassium efflux via the voltage-gated potassium channel KV1.3 mediates ASC oligomerization. This is followed by caspase 1 cleavage and downstream activation of pore-forming gasdermin D, enabling cytosolic release of S100A8/S100A9. Strikingly, E-selectin-mediated gasdermin D pore formation does not result in cell death but is a transient process involving activation of the ESCRT III membrane repair machinery. These data clarify molecular mechanisms of controlled S100A8/S100A9 release from neutrophils and identify the NLRP3/gasdermin D axis as a rapid and reversible activation system in neutrophils during inflammation.

DOI: 10.1038/s41590-023-01656-1

Source: https://www.nature.com/articles/s41590-023-01656-1