STAT1-driven FcRn suppression in macrophages limits antibody protection during bacterial sepsis

Sepsis is frequently accompanied by reduced circulating IgG levels, but the mechanism and therapeutic implications remain unclear. Here, we show that bacterial sepsis accelerates clearance of both endogenous and therapeutic IgG independently of antigen specificity. Lipopolysaccharide and peptidoglycan activate STAT1 in hepatic and splenic macrophages, leading to selective downregulation of the neonatal Fc receptor (FcRn), impaired IgG recycling, and enhanced intracellular degradation. Macrophage-specific deletion of Fcgrt abolishes sepsis-induced IgG loss, whereas genetic or pharmacologic inhibition of STAT1 restores FcRn expression, preserves circulating IgG, and enhances the protective efficacy of intravenous immunoglobulin and pathogen-specific monoclonal antibodies. In human sepsis, reduced FcRn expression in monocytes correlates with poor outcome, and bacterial or PAMP stimulation suppresses FcRn and IgG transcytosis in primary macrophages in a STAT1-dependent manner. These findings identify STAT1-driven suppression of macrophage FcRn as a conserved mechanism limiting antibody protection during bacterial sepsis.