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Neutrophils disrupt B-1a cell homeostasis by targeting Siglec-G to exacerbate sepsis

Cellular & Molecular Immunology volume 21, pages 707–722 (2024)Cite this article

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Abstract

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.

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Acknowledgements

We prepared schematic figures using BioRender.

Funding

This work was supported in part by National Institutes of Health (NIH) grants R35GM118337 (PW) and R01GM129633 (MA) as well as the Research Investigator Fellowship from the Shock Society (CT).

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  1. These authors contributed equally: Monowar Aziz, Ping Wang.

Authors and Affiliations

  1. Center for Immunology and Inflammation, the Feinstein Institutes for Medical Research, Manhasset, New York, USA

    Chuyi Tan, Bridgette Reilly, Gaifeng Ma, Atsushi Murao, Alok Jha, Monowar Aziz & Ping Wang

  2. Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, China

    Chuyi Tan

  3. Departments of Surgery and Molecular Medicine, Zucker School of Medicine at Hofstra/Northwell, Manhasset, New York, USA

    Monowar Aziz & Ping Wang

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  1. Chuyi Tan
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Contributions

Conceptualization: CT, MA, PW; Methodology: CT, BR, GM, AM, AJ, MA, PW; Investigation: CT, BR, GM, AM, AJ, MA, PW; Visualization: CT, MA, PW; Funding acquisition: MA, PW; Project administration: MA, PW; Supervision: MA, PW; Writing—original draft: CT, MA; Writing—review & editing: CT, BR, MA, AM, PW.

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Correspondence to Monowar Aziz or Ping Wang.

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Tan, C., Reilly, B., Ma, G. et al. Neutrophils disrupt B-1a cell homeostasis by targeting Siglec-G to exacerbate sepsis. Cell Mol Immunol 21, 707–722 (2024). https://doi.org/10.1038/s41423-024-01165-7

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