Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA, USA; Institute for Immunology, University of California, Irvine, Irvine, CA, USA.
Department of Ophthalmology, University of California, Irvine, Irvine, CA, USA.
Cell Rep. 2021 May 18;35(7):109139. doi: 10.1016/j.celrep.2021.109139.
Neutrophils are an important source of interleukin (IL)-1β and other cytokines because they are recruited to sites of infection and inflammation in high numbers. Although secretion of processed, bioactive IL-1β by neutrophils is dependent on NLRP3 and Gasdermin D (GSDMD), IL-1α secretion by neutrophils has not been reported. In this study, we demonstrate that neutrophils produce IL-1α following injection of Aspergillus fumigatus spores that express cell-surface β-glucan. Although IL-1α secretion by lipopolysaccharide (LPS)/ATP-activated macrophages and dendritic cells is GSDMD dependent, IL-1α secretion by β-glucan-stimulated neutrophils occurs independently of GSDMD. Instead, we found that bioactive IL-1α is in exosomes that were isolated from cell-free media of β-glucan-stimulated neutrophils. Further, the exosome inhibitor GW4869 significantly reduces IL-1α in extracellular vesicles (EVs) and total cell-free supernatant. Together, these findings identify neutrophils as a source of IL-1α and demonstrate a role for EVs, specifically exosomes, in neutrophil secretion of bioactive IL-1α.
中性粒细胞是白细胞介素 (IL)-1β 和其他细胞因子的重要来源，因为它们大量募集到感染和炎症部位。尽管中性粒细胞中经加工的、有生物活性的 IL-1β 的分泌依赖于 NLRP3 和 Gasdermin D (GSDMD)，但中性粒细胞分泌 IL-1α 尚未见报道。在这项研究中，我们证明了在表达细胞表面β-葡聚糖的烟曲霉孢子注射后，中性粒细胞会产生 IL-1α。虽然 LPS/ATP 激活的巨噬细胞和树突状细胞中 IL-1α 的分泌依赖于 GSDMD，但β-葡聚糖刺激的中性粒细胞中 IL-1α 的分泌不依赖于 GSDMD。相反，我们发现生物活性的 IL-1α 存在于从β-葡聚糖刺激的中性粒细胞无细胞培养基中分离出的外泌体中。此外，外泌体抑制剂 GW4869 可显著减少细胞外囊泡 (EVs) 和总无细胞上清液中的 IL-1α。总之，这些发现确定了中性粒细胞是 IL-1α 的来源，并证明了 EVs（特别是外泌体）在中性粒细胞分泌生物活性 IL-1α 中的作用。
