Work

A RIPK2-associated macrophage program links mycobacterial sensing to osteoclastogenesis in bone tuberculosis

Year: 2026

Type: article

Abstract: Introduction In bone tuberculosis, Mycobacterium tuberculosis (Mtb) infection triggers inflammatory bone destruction, but the macrophage programs that convert Mtb signals into osteoclastogenesis remain poorly defined. Methods We generated single-cell RNA-seq data from human spinal tuberculosis lesions and integrated them with public H3K27ac ChIP-seq, RNA-seq, Hi-C, and motif data. Key findings were validated in primary macrophages stimulated with Mtb lysate. Results We identified 64 Mtb-induced super-enhancers, and integrated analysis prioritized RIPK2 as a candidate. Lesion-associated myeloid populations showed enhanced inflammatory and osteoclast-priming signatures, followed a mononuclear phagocyte-to-osteoclast trajectory, and exhibited a linear correlation between RIPK2 expression and osteoclast score. In mice, RIPK2 localized to CTSK-positive bone interfaces. In vitro , Mtb stimulation induced Il1b, Nfkbiz , and Tnfrsf11a expression, IL-1β secretion, and surface RANK upregulation; these responses were suppressed by the RIPK2 inhibitor GSK583. Discussion These findings link RIPK2 to both macrophage inflammatory signaling and osteoclastogenesis in bone tuberculosis, suggesting that RIPK2 may be a target for limiting infection-driven bone destruction.

Source: Frontiers in Cellular and Infection Microbiology

DOI: 10.3389/fcimb.2026.1970405