Ubiquitin-Specific Peptidase 8 Is Critical for the Onset of Infectious Osteomyelitis by Targeting RIPK2 Ubiquitination

Abstract

Receptor interacting serine/threonine kinase (RIPK) 2 is associated with cellular inflammation and immune regulation. The current study explored the roles of RIPK2 in osteomyelitis and the potential upstream targets of RIPK2. S. aureus-induced osteomyelitis mouse model was established in the wide-type (WT) and ubiquitin specific peptidase 8 (USP8)-deficient (USP -/-) mice and osteomyelitis-related symptoms were evaluated. Bone marrow-derived macrophages (BMDMs) were isolated from WT and USP -/mice. ELISAs, qPCR, and immunoblot analysis were used to determine the levels of target biomarkers, which were induced by lipopolysaccharide (LPS), CpG or PAM3CSK4. USP8 promoted RIPK2-mediated NF-κB activation. USP8 was indispensable for RIPK2-mediated NF-κB activation induced by LPS in the BMDMs. The presence of USP8 was required for the production of inflammatory cytokines induced by LPS, CpG or PAM3CSK4 in the BMDMs. In addition, USP -/mice exhibited ameliorated symptoms including less bodyweight and cortical bone loss, and reduced bacterial load and reactive bone formation, in S. aureus-induced osteomyelitis mouse model. USP8 is critical in the S. aureus-induced osteomyelitis mouse model by targeting RIPK2 ubiquitination.