Neuregulin 4 inhibits synovial macrophage pro-inflammatory polarization via ErbB4/Stat5b/NF-κB signaling to alleviate osteoarthritis progression.

Osteoarthritis (OA) is a chronic inflammatory disease characterized by synovial inflammation and cartilage degradation. Synovial macrophages, as a key driver of OA progression, during all stages of OA and induced to produce inflammatory cytokines that aggravate the degradation of cartilage. Here, we demonstrate that neuregulin-4 (Nrg4) deficiency exacerbates synovial pro-inflammatory macrophage transformation and articular cartilage abrasion in a mouse model of OA. Conversely, Nrg4 re-expression significantly reduces pro-inflammatory macrophage accumulation and synovial inflammation, thereby attenuating OA progression. Mechanistically, Nrg4 activates the ErbB4/Stat5b signaling pathway, which subsequently suppresses NF-κB activation, leading to reduced pro-inflammatory macrophage transformation and pro-inflammatory cytokine production. In vitro experiments further confirm that Nrg4 directly inhibits macrophage infiltration. These findings reveal a novel role for Nrg4 in modulating synovial macrophage transformation through the ErbB4/Stat5b/NF-κB axis, offering a potential therapeutic strategy for OA by targeting synovial inflammation. This study also expands our understanding of OA protection beyond chondrocyte protection, emphasizing its role in regulating the synovial microenvironment and cartilage homeostasis in OA.