NOD2 attenuates osteoarthritis via reprogramming the activation of synovial macrophages
Changchuan Li1, Zhuji Ouyang1, Yuhsi Huang1
1Department of Orthopaedic Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China.
Objective:
Synovial inflammation, which precedes other pathological changes in osteoarthritis (OA), is primarily initiated by activation and M1 polarization of macrophages. While macrophages play a pivotal role in the inflammatory process of OA, the mechanisms underlying their activation and polarization remain incompletely elucidated. This study aims to investigate the role of NOD2 as a reciprocal modulator of HMGB1/TLR4 signaling in macrophage activation and polarization during OA pathogenesis.
Design:
We examined NOD2 expression in the synovium and determined the impact of NOD2 on macrophage activation and polarization by knockdown and overexpression models in vitro. Paracrine effect of macrophages on fibroblast-like synoviocytes (FLS) and chondrocytes was evaluated under conditions of NOD2 overexpression. Additionally, the in vivo effect of NOD2 was assessed using collagenase VII induced OA model in mice.
Results:
Expression of NOD2 was elevated in osteoarthritic synovium. In vitro experiments demonstrated that NOD2 serves as a negative regulator of HMGB1/TLR4 signaling pathway. Furthermore, NOD2 overexpression hampered the inflammatory paracrine effect of macrophages on FLS and chondrocytes. In vivo experiments revealed that NOD2 overexpression mitigated OA in mice.
Conclusions:
Supported by convincing evidence on the inhibitory role of NOD2 in modulating the activation and M1 polarization of synovial macrophages, this study provided novel insights into the involvement of innate immunity in OA pathogenesis and highlighted NOD2 as a potential target for the prevention and treatment of OA.
Insights
NOD2 inhibits macrophage activation and M1 polarization in osteoarthritis (OA) by negatively regulating HMGB1/TLR4 signaling. This finding suggests NOD2 as a potential therapeutic target for OA prevention and treatment.
Area of Science:
- Immunology
- Pathology
- Molecular Biology
Background:
- Synovial inflammation is an early pathological event in osteoarthritis (OA).
- Macrophage activation and M1 polarization are key drivers of synovial inflammation in OA.
- Mechanisms regulating macrophage activation and polarization in OA are not fully understood.
Purpose of the Study:
- To investigate the role of NOD2 in modulating macrophage activation and polarization.
- To explore the relationship between NOD2 and the HMGB1/TLR4 signaling pathway in OA pathogenesis.
- To assess the therapeutic potential of NOD2 in OA.
Main Methods:
- Examined NOD2 expression in human osteoarthritic synovium.
- Utilized in vitro knockdown and overexpression models to study NOD2's effect on macrophage activation and polarization.
- Evaluated the paracrine effects of macrophages on fibroblast-like synoviocytes (FLS) and chondrocytes.
- Assessed the in vivo efficacy of NOD2 in a collagenase-induced mouse model of OA.
Main Results:
- NOD2 expression was upregulated in osteoarthritic synovium.
- NOD2 acted as a negative regulator of the HMGB1/TLR4 signaling pathway in vitro.
- NOD2 overexpression reduced the inflammatory paracrine effects of macrophages on FLS and chondrocytes.
- In vivo, NOD2 overexpression ameliorated OA in mice.
Conclusions:
- NOD2 plays an inhibitory role in the activation and M1 polarization of synovial macrophages.
- This study offers novel insights into the innate immune system's involvement in OA.
- NOD2 represents a promising therapeutic target for OA prevention and treatment.
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