2. Academic Validation
  3. Honokiol suppresses the aberrant interactions between renal resident macrophages and tubular epithelial cells in lupus nephritis through the NLRP3/IL-33/ST2 axis

Honokiol suppresses the aberrant interactions between renal resident macrophages and tubular epithelial cells in lupus nephritis through the NLRP3/IL-33/ST2 axis

  • Cell Death Dis. 2023 Mar 1;14(3):174. doi: 10.1038/s41419-023-05680-9.
Qing Ma 1,  Mengyang Xu 2,  Xin Jing 3,  Jiang Qiu 4,  Shuo Huang 5,  Honghao Yan 6,  Lu Yin 7,  Jiang Lou 8,  Lisha Zhao 9,  Yongsheng Fan 10,  Ping Qiu 11
Affiliations

Affiliations

  • 1 The First School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, China.
  • 2 School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, China.
  • 3 Department of Clinical Laboratory, Tongde Hospital of Zhejiang Province, Hangzhou, China.
  • 4 Department of Medicine, Hangzhou Normal University, Hangzhou, China.
  • 5 School of Pharmaceutial Science, Zhejiang Chinese Medical University, Hang zhou, China.
  • 6 School of Basic Medical Sciences, Zhejiang Chinese Medicine University, Hang zhou, China.
  • 7 Department of Pathology, Affiliated Hangzhou First People's Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
  • 8 Department of Pharmacy, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 9 Department of Medicine, Zhejiang Academy of Traditional Chinese Medicine, Hang zhou, China. 1669763749@qq.com.
  • 10 The First School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, China. fyszjtcm@163.com.
  • 11 School of Pharmaceutial Science, Zhejiang Chinese Medical University, Hang zhou, China. dongguacha126@126.com.
PMID: 36859530 DOI: 10.1038/s41419-023-05680-9
Abstract

Lupus nephritis (LN) is a type of immune-complex nephritis caused by systemic lupus erythematosus and is a major contributor to mortality and morbidity. Honokiol (HNK) has been found to have a therapeutic effect on LN, but its action mechanism remains unclear. In this study, we first demonstrated that HNK attenuates kidney injury in MRL/lpr mice. Results from RNA Sequencing combined with ingenuity pathway analysis suggested that HNK plays an anti-LN role through inhibition of the NLRP3 inflammasome and IL33. GEO chip data, single-cell data, and clinical samples from LN patients demonstrated that the Pyroptosis and IL-33/ST2 pathways are abnormally activated during the stage of LN. In vivo, similar to the results of the AAV-mediated NLRP3 shRNA MRL/lpr model, HNK downregulated serum and renal IL-33 levels, and suppressed NLRP3 inflammasome and the IL-33/ST2 axis in the kidney. In vitro, co-culturing NLRP3-overexpressing or IL-33 knocked-down rat renal macrophages with NRK-52E cells confirmed that NLRP3 activation in resident macrophages directly upregulates IL-33, which in turn mediates the IL-33/ST2/NF-κB pathway to promote the inflammatory response of renal tubular epithelial cells. Furthermore, a molecular docking model and surface plasmon resonance analysis were utilized to demonstrate a direct interaction between HNK and NLRP3. In conclusion, this study provides a novel anti-LN treatment strategy in which HNK plays a preventive and therapeutic role against LN by suppressing the abnormal crosstalk between renal resident macrophages and renal tubular epithelial cells by inhibiting the activation of the NLRP3/IL-33/ST2 axis.

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