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 ...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.展开更多
基金supported in part by National Institutes of Health(NIH)grants R35GM118337(PW)and R01GM129633(MA)the Research Investigator Fellowship from the Shock Society(CT).
文摘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.
