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已发表论文
尼古丁通过α7nAChR介导抑制HMGB1/TLR4/NF-κB信号通路减轻软骨细胞炎症
Authors Lin S, Liu T, Song G, Pan H
Received 10 June 2025
Accepted for publication 3 November 2025
Published 19 November 2025 Volume 2025:18 Pages 16157—16168
DOI https://doi.org/10.2147/JIR.S545945
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 3
Editor who approved publication: Dr Ujjwol Risal
Silong Lin, Tao Liu, Gaoming Song, Hong Pan
Department of Orthopaedics, Anqing First People’s Hospital of Anhui Medical University, Anqing, Anhui, People’s Republic of China
Correspondence: Hong Pan, Email 18133027706@163.com
Background: Chondrocyte inflammation is a major driver of osteoarthritis (OA). The cholinergic anti-inflammatory pathway (CAP) exhibits significant anti-inflammatory effects, with the α 7 nicotinic acetylcholine receptor (α 7nAChR) playing a pivotal role. However, it remains unclear whether α 7nAChR alleviates chondrocyte inflammation through the regulation of the high mobility group box 1 (HMGB1)/TLR4/NF-κB signaling pathway.
Methods: An in vitro model of chondrocyte inflammation was established by lipopolysaccharide (LPS) treatment of mouse cartilage cells. The protective effects of various concentrations of nicotine (Nic) on chondrocytes were assessed using the CCK-8 assay. To verify the critical role of α 7nAChR, groups treated with methyllycaconitine (MLA, an α 7nAChR antagonist) and siRNA-α 7nAChR were included. Immunofluorescence was employed to observe the localization and expression of α 7nAChR, HMGB1, and P65. Additionally, qRT-PCR, Western blot, and ELISA were employed to detect the expression of inflammation-related factors, cytokines, and MMPs.
Results: The CCK-8 assay indicated that 1000 nmol/L Nic significantly restored chondrocyte proliferation activity reduced by LPS stimulation (P < 0.01). Immunofluorescence, Western blot, and qRT-PCR results demonstrated that Nic markedly enhanced α 7nAChR expression and inhibited LPS-induced nuclear translocation of HMGB1, as well as the expression of TLR4 and P65. The anti-inflammatory effects of Nic were significantly diminished following MLA treatment or siRNA-mediated knockdown of α 7nAChR (P < 0.01). Furthermore, ELISA assays demonstrated that Nic suppressed the secretion of IL-1β, TNF-α, MMP-2, and MMP-9, an effect dependent on α 7nAChR activation.
Conclusion: This study reveals that Nic alleviates chondrocyte inflammatory responses by activating α 7nAChR and inhibiting the HMGB1/TLR4/NF-κB signaling pathway. These findings not only enhance the understanding of CAP’s role in OA inflammation regulation but also provide a theoretical basis for exploring α 7nAChR as a potential anti-inflammatory target. However, since the research is currently limited to in vitro cellular studies, further animal experiments are necessary to validate its clinical translational potential.
Keywords: nicotine, α 7nAChR, HMGB1/TLR4/NF-κB pathway, chondrocyte inflammation, osteoarthritis
Department of Orthopaedics, Anqing First People’s Hospital of Anhui Medical University, Anqing, Anhui, People’s Republic of China
Correspondence: Hong Pan, Email 18133027706@163.com
Background: Chondrocyte inflammation is a major driver of osteoarthritis (OA). The cholinergic anti-inflammatory pathway (CAP) exhibits significant anti-inflammatory effects, with the α 7 nicotinic acetylcholine receptor (α 7nAChR) playing a pivotal role. However, it remains unclear whether α 7nAChR alleviates chondrocyte inflammation through the regulation of the high mobility group box 1 (HMGB1)/TLR4/NF-κB signaling pathway.
Methods: An in vitro model of chondrocyte inflammation was established by lipopolysaccharide (LPS) treatment of mouse cartilage cells. The protective effects of various concentrations of nicotine (Nic) on chondrocytes were assessed using the CCK-8 assay. To verify the critical role of α 7nAChR, groups treated with methyllycaconitine (MLA, an α 7nAChR antagonist) and siRNA-α 7nAChR were included. Immunofluorescence was employed to observe the localization and expression of α 7nAChR, HMGB1, and P65. Additionally, qRT-PCR, Western blot, and ELISA were employed to detect the expression of inflammation-related factors, cytokines, and MMPs.
Results: The CCK-8 assay indicated that 1000 nmol/L Nic significantly restored chondrocyte proliferation activity reduced by LPS stimulation (P < 0.01). Immunofluorescence, Western blot, and qRT-PCR results demonstrated that Nic markedly enhanced α 7nAChR expression and inhibited LPS-induced nuclear translocation of HMGB1, as well as the expression of TLR4 and P65. The anti-inflammatory effects of Nic were significantly diminished following MLA treatment or siRNA-mediated knockdown of α 7nAChR (P < 0.01). Furthermore, ELISA assays demonstrated that Nic suppressed the secretion of IL-1β, TNF-α, MMP-2, and MMP-9, an effect dependent on α 7nAChR activation.
Conclusion: This study reveals that Nic alleviates chondrocyte inflammatory responses by activating α 7nAChR and inhibiting the HMGB1/TLR4/NF-κB signaling pathway. These findings not only enhance the understanding of CAP’s role in OA inflammation regulation but also provide a theoretical basis for exploring α 7nAChR as a potential anti-inflammatory target. However, since the research is currently limited to in vitro cellular studies, further animal experiments are necessary to validate its clinical translational potential.
Keywords: nicotine, α 7nAChR, HMGB1/TLR4/NF-κB pathway, chondrocyte inflammation, osteoarthritis