- Preprint Article
- 10.65215/ltspreprints.2026.02.12.000130
Antibody efficacy in bacterial sepsis is rescued by targeting macrophage PAMP-STAT1-FcRn axis
- Feb 13, 2026
- Xinyu Wei + 19 more +19
Sepsis induces a significant loss of circulating IgG, but the underlying mechanism has remained obscure. Here, we identify a previously unrecognized pathogenic axis that directly links bacterial PAMPs to antibody failure. During bacterial sepsis, LPS and PGN potently activate macrophage STAT1, which in turn transcriptionally silences FcRn, collapsing IgG salvage pathways and driving rapid antibody catabolism. This IgG-destabilizing mechanism is strikingly macrophage-specific in the mouse liver and spleen and is conserved in human macrophages. Loss of macrophage FcRn ablates the antibody protection, whereas inhibition of Toll-like receptor 4 (TLR4) or STAT1 signaling potently enhances antibody efficacy in septic mice. These findings uncover a fundamental mechanism of sepsis-induced immunosuppression and reveal a tractable intervention point for rescuing antibody therapeutics against bacterial sepsis.
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