Molecular immunology · 2026
NSUN2 aggravates M1 macrophage polarization in arthritis progression through m5C modification of CCL2.
СтатьяНазвание и аннотация: Перевод в очереди
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He Chunlei, Zhang Junhua, Deli Geer, Zhao Kai, Liu Lulin, Lai Baojian, Hu Meiyu, He Huabin
Аннотация
BACKGROUND: Arthritis is an inflammatory disease characterized by multifactorial pathogenesis in joints or surrounding tissues. M1 macrophage polarization is a key pathological feature of arthritis, and m⁵C RNA modification has been implicated in disease progression. This study aimed to elucidate the role of NSUN2, a writer of m⁵C modification, in modulating arthritis development.
METHODS: LPS-stimulated RAW264.7 cell models and collagen-induced arthritis (CIA) rat models were established. M1 and M2 macrophage polarization was assessed by detecting cell surface markers and pro-inflammatory cytokines using immunofluorescence, enzyme-linked immunosorbent assay (ELISA), Western blot, and quantitative real-time PCR. Underlying mechanisms were investigated via methylated RNA immunoprecipitation (MeRIP), Co-immunoprecipitation (Co-IP), and Dual-Luciferase reporter assays.
RESULTS: Downregulation of NSUN2 significantly inhibited M1 polarization and promoted M2 activation both in vitro and in vivo. NSUN2 enhanced m5C modification of CCL2, stabilized its mRNA expression, and facilitated its interaction with CCR2. Furthermore, NSUN2 activated the NF-κB signaling pathway in macrophages. Notably, inhibition of CCL2 activity abrogated the effects of NSUN2 on macrophage polarization.
CONCLUSION: NSUN2 drives M1 macrophage polarization through m5C modification of CCL2, thereby exacerbating arthritis progression. Targeting NSUN2 may alleviate inflammatory responses, offering a novel therapeutic strategy for arthritis treatment.
METHODS: LPS-stimulated RAW264.7 cell models and collagen-induced arthritis (CIA) rat models were established. M1 and M2 macrophage polarization was assessed by detecting cell surface markers and pro-inflammatory cytokines using immunofluorescence, enzyme-linked immunosorbent assay (ELISA), Western blot, and quantitative real-time PCR. Underlying mechanisms were investigated via methylated RNA immunoprecipitation (MeRIP), Co-immunoprecipitation (Co-IP), and Dual-Luciferase reporter assays.
RESULTS: Downregulation of NSUN2 significantly inhibited M1 polarization and promoted M2 activation both in vitro and in vivo. NSUN2 enhanced m5C modification of CCL2, stabilized its mRNA expression, and facilitated its interaction with CCR2. Furthermore, NSUN2 activated the NF-κB signaling pathway in macrophages. Notably, inhibition of CCL2 activity abrogated the effects of NSUN2 on macrophage polarization.
CONCLUSION: NSUN2 drives M1 macrophage polarization through m5C modification of CCL2, thereby exacerbating arthritis progression. Targeting NSUN2 may alleviate inflammatory responses, offering a novel therapeutic strategy for arthritis treatment.