Neutrophils Disrupt B-1a Cell Homeostasis by Targeting Siglec-G to Exacerbate Sepsis

Abstract

Abstract In sepsis, B-1a cells diminish in the peritoneal cavity (PerC) as they relocate to the spleen via CXCL12/CXCR4. In the spleen, these cells differentiate into plasma cells, skewing from innate to adaptive phenotype. The mechanism governing the PerC B-1a cell relocation in sepsis remains elusive. Sialic-acid-binding immunoglobulin-like lectin (Siglec)-G is a B-1a cell-specific receptor. We found that Siglec-G-/- PerC B-1a cells had a higher migration rate than WT B-1a cells. Siglec-G negatively regulated B-1a cell migration by interacting with CXCR4, as Siglec-G-/- B-1a cells showed increased activation of the CXCR4’s downstream pathway. LPS-activated neutrophils decreased Siglec-G expression on B-1a cells and promoted B-1a cell migration, while NE inhibitor reversed these. Recombinant NE treatment decreased Siglec-G expression by cleavage on B-1a cells. A small Siglec-G-derived decoy peptide (SDP) was developed to prevent Siglec-G cleavage based on the interaction site of NE at the Siglec-G protein in silico. Treatment of SDP significantly reduced the decrease in PerC B-1a cell numbers and Siglec-G expression on B-1a cells in septic mice. SDP treatment significantly reduced serum IL-6 and TNFα levels and improved survival rates in septic mice. In conclusion, we discover Siglec-G to be a new regulator of B-1a cell migration. Preventing NE-mediated Siglec-G cleavage upholds a promising strategy for maintaining peritoneal B-1a cell homeostasis to mitigate sepsis.