SR9009 attenuates inflammation-related NPMSC pyroptosis and IVDD through NR1D1/NLRP3/IL-1β pathway

Ze-Nan Huang; Jing Wang; Ze-Yu Wang; Ling-Yuan Min; Hai-Ling Ni; Yan-Ling Han; You-Yue Tian; Ya-Zhou Cui; Jing-Xiang Han; Xiao-Fei Cheng

doi:10.1016/j.isci.2024.109733

SR9009 attenuates inflammation-related NPMSC pyroptosis and IVDD through NR1D1/NLRP3/IL-1β pathway

iScience. 2024 Apr 16;27(5):109733. doi: 10.1016/j.isci.2024.109733. eCollection 2024 May 17.

Authors

Ze-Nan Huang¹, Jing Wang², Ze-Yu Wang³, Ling-Yuan Min⁴, Hai-Ling Ni¹, Yan-Ling Han⁵, You-Yue Tian⁶, Ya-Zhou Cui², Jing-Xiang Han¹, Xiao-Fei Cheng⁷

Affiliations

¹ Department of Orthopedics, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 200072, Shandong Province, China.
² Department of Orthopedic Surgery, The First Affiliated Hospital of Shandong First Medical University, Jinan 200072, Shandong Province, China.
³ Department of Spine Surgery, Affiliated Nanjing Jiangbei Hospital of Xinglin College, Nantong University, Nanjing 210019, Jiangsu Province, China.
⁴ Research Center of Translational Medicine, Central Hospital Affiliated to Shandong First Medical University, Jinan 200072, Shandong Province, China.
⁵ Medical Experimental Research Center, Yangzhou University, Yangzhou 225001, Jiangsu Province, China.
⁶ Department of Pharmacy, University of South China, Hengyang 421001, Hunan Province, China.
⁷ Department of Orthopaedic Surgery, Shanghai Key Laboratory of Orthopedic Implants, Shanghai Ninth People's Hospital affiliated to Shanghai JiaoTong University School of Medicine, Shanghai 200011, China.

Abstract

Intervertebral disc is a highly rhythmical tissue. As a key factor linking biorhythm and inflammatory response, the shielding effect of NR1D1 in the process of intervertebral disc degeneration remains unclear. Here, we first confirmed that NR1D1 in the nucleus pulposus tissue presents periodic rhythmic changes and decreases in expression with intervertebral disc degeneration. Second, when NR1D1 was activated by SR9009 in vitro, NLRP3 inflammasome assembly and IL-1β production were inhibited, while ECM synthesis was increased. Finally, the vivo experiments further confirmed that the activation of NR1D1 can delay the process of disc degeneration to a certain extent. Mechanistically, we demonstrate that NR1D1 can bind to IL-1β and NLRP3 promoters, and that the NR1D1/NLRP3/IL-1β pathway is involved in this process. Our results demonstrate that the activation of NR1D1 can effectively reduce IL-1β secretion, alleviate LPS-induced NPMSC pyroptosis, and protect ECM degeneration.

Keywords: Cell biology; Molecular biology; Orthopedics.