Identification of procathepsin L (pCTS-L)-neutralizing monoclonal antibodies to treat potentially lethal sepsis.

Abstract

Antibody-based strategies have been attempted to antagonize early cytokines of sepsis, but not yet been tried to target inducible late-acting mediators. Here, we report that the expression and secretion of procathepsin-L (pCTS-L) was induced by serum amyloid A (SAA) in innate immune cells, contributing to its late and systemic accumulation in experimental and clinical sepsis. Recombinant pCTS-L induced interleukin-6 (IL-6), IL-8, GRO-α/KC, GRO-β/MIP-2, and MCP-1 release in innate immune cells and moderately correlated with blood concentrations of these cytokines/chemokines in clinical sepsis. Mechanistically, pCTS-L interacted with Toll-like receptor 4 (TLR4) and the receptor for advanced glycation end products (RAGE) to induce cytokines/chemokines. Pharmacological suppression of pCTS-L with neutralizing polyclonal and monoclonal antibodies attenuated pCTS-L-mediated inflammation by impairing its interaction with TLR4 and RAGE receptors, and consequently rescued animals from lethal sepsis. Our findings have suggested a possibility of developing antibody strategies to prevent dysregulated immune responses mediated by late-acting cytokines.

• Authors: Cassie Shu Zhu, Xiaoling Qiang, Weiqiang Chen, Jianhua Li, Xiqian Lan, Huan Yang, Jonathan Gong, Lance Becker, Ping Wang, Kevin J Tracey, Haichao Wang
• Journal: Science advances (Sci Adv) Vol. 9 Issue 5 Pg. eadf4313 (02 03 2023) ISSN: 2375-2548 [Electronic] United States
• PMID: 36735789 (Publication Type: Journal Article)

Chemical References

• procathepsin L
• Toll-Like Receptor 4
• Antibodies, Monoclonal
• Cytokines
• Receptor for Advanced Glycation End Products
• Chemokines

Topics

• Animals
• Toll-Like Receptor 4 (metabolism)
• Antibodies, Monoclonal (pharmacology, therapeutic use)
• Cytokines
• Receptor for Advanced Glycation End Products
• Chemokines (metabolism)
• Sepsis