Center for Immunology and Inflammation, the Feinstein Institutes for Medical Research, Manhasset, New York, USA.
Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, China.
Cell Mol Immunol. 2024 Jul;21(7):707-722. doi: 10.1038/s41423-024-01165-7. Epub 2024 May 24.
B-1a cells, an innate-like cell population, are crucial for pathogen defense and the regulation of inflammation through their release of natural IgM and IL-10. In sepsis, B-1a cell numbers are decreased in the peritoneal cavity as they robustly migrate to the spleen. Within the spleen, migrating B-1a cells differentiate into plasma cells, leading to alterations in their original phenotype and functionality. We discovered a key player, sialic acid-binding immunoglobulin-like lectin-G (Siglec-G), which is expressed predominantly on B-1a cells and negatively regulates B-1a cell migration to maintain homeostasis. Siglec-G interacts with CXCR4/CXCL12 to modulate B-1a cell migration. Neutrophils aid B-1a cell migration via neutrophil elastase (NE)-mediated Siglec-G cleavage. Human studies revealed increased NE expression in septic patients. We identified an NE cleavage sequence in silico, leading to the discovery of a decoy peptide that protects Siglec-G, preserves peritoneal B-1a cells, reduces inflammation, and enhances sepsis survival. The role of Siglec-G in inhibiting B-1a cell migration to maintain their inherent phenotype and function is compromised by NE in sepsis, offering valuable insights into B-1a cell homeostasis. Employing a small decoy peptide to prevent NE-mediated Siglec-G cleavage has emerged as a promising strategy to sustain peritoneal B-1a cell homeostasis, alleviate inflammation, and ultimately improve outcomes in sepsis patients.
B-1a 细胞是一种先天样细胞群体，通过释放天然 IgM 和 IL-10，对于病原体防御和炎症调节至关重要。在败血症中，B-1a 细胞数量在腹腔中减少，因为它们强烈迁移到脾脏。在脾脏中，迁移的 B-1a 细胞分化为浆细胞，导致其原始表型和功能发生改变。我们发现了一个关键的调节因子，唾液酸结合免疫球蛋白样凝集素-G（Siglec-G），它主要在 B-1a 细胞上表达，并负调控 B-1a 细胞迁移，以维持内稳态。Siglec-G 通过与 CXCR4/CXCL12 相互作用来调节 B-1a 细胞迁移。中性粒细胞通过中性粒细胞弹性蛋白酶（NE）介导的 Siglec-G 裂解来辅助 B-1a 细胞迁移。人类研究表明，败血症患者的 NE 表达增加。我们通过计算机分析鉴定出了一个 NE 裂解序列，从而发现了一个诱饵肽，它可以保护 Siglec-G，维持腹膜 B-1a 细胞，减轻炎症，提高败血症的存活率。在败血症中，NE 破坏 Siglec-G 抑制 B-1a 细胞迁移以维持其固有表型和功能的作用，这为 B-1a 细胞内稳态提供了有价值的见解。使用小的诱饵肽来防止 NE 介导的 Siglec-G 裂解已成为维持腹膜 B-1a 细胞内稳态、减轻炎症并最终改善败血症患者预后的有前途的策略。
