Neutrophil-derived apoptotic bodies function as decoy signals to preserve bone integrity during infectious osteomyelitis.

Abstract

Bone infection represents a pathological intersection of immunity and skeletal remodeling, where inflammatory responses drive excessive bone loss. Neutrophils dominate the early immune infiltration during infection, yet how neutrophil fate within infected bone marrow influences disease progression remains poorly understood. Here, we identify neutrophil-derived apoptotic bodies (Neut-ABs) as key mediators of bone protection during infectious osteomyelitis. Bone infection triggers extensive neutrophil apoptosis, resulting in the accumulation of Neut-ABs. Integrated transcriptomic and proteomic profiling of these Neut-ABs revealed significant enrichment of TLR2 and the sialyltransferase ST3GAL1, and lectin blotting confirmed that TLR2 is modified with α2,3-linked sialic acids. Mechanistically, α2,3-sialylated TLR2 on Neut-ABs functions as a molecular decoy that competitively interferes with Siglec15-TLR2 interactions in osteoclast precursors, thereby preventing precursor fusion and suppressing bone-resorptive activity. This inhibitory effect requires both the formation and sialylation of Neut-ABs, as it was abolished in Fas-deficient (MRL/Lpr) mice, upon neuraminidase-mediated desialylation, or when using Neut-ABs derived from Tlr2^⁻/⁻ mice. Therapeutic delivery of Neut-ABs markedly attenuates osteolysis in infected mice without altering bacterial clearance. These findings uncover a neutrophil-to-bone signaling axis in which sialylated vesicular decoys selectively suppress osteoclast activation, illuminating a new paradigm linking innate immune turnover to skeletal homeostasis.