2. Academic Validation
  3. Sp1 S-Sulfhydration Induced by Hydrogen Sulfide Inhibits Inflammation via HDAC6/MyD88/NF-κB Signaling Pathway in Adjuvant-Induced Arthritis

Sp1 S-Sulfhydration Induced by Hydrogen Sulfide Inhibits Inflammation via HDAC6/MyD88/NF-κB Signaling Pathway in Adjuvant-Induced Arthritis

  • Antioxidants (Basel). 2022 Apr 7;11(4):732. doi: 10.3390/antiox11040732.
Meng Li 1 2,  Wei Hu 1,  Ran Wang 1,  Zhaoyi Li 1,  Yue Yu 1,  Yue Zhuo 1 3,  Yida Zhang 1 4,  Zhou Wang 1,  Yuanye Qiu 1,  Keyuan Chen 1,  Qian Ding 1,  Wei Qi 1,  Menglin Zhu 1,  Yizhun Zhu 1 5 6
Affiliations

Affiliations

  • 1 State Key Laboratory of Quality Research in Chinese Medicine, Faculty of Chinese Medicine, Macau University of Science and Technology, Macau 999078, China.
  • 2 Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, China.
  • 3 Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou 510006, China.
  • 4 State Key Laboratory of Respiratory Disease, National Clinical Center for Respiratory Diseases, Guangzhou Institute of Respiratory Diseases, First Affiliated Hospital, Guangzhou Medical University, Guangzhou 510120, China.
  • 5 School of Pharmacy, Macau University of Science and Technology, Macau 999078, China.
  • 6 Shanghai Key Laboratory of Bioactive Small Molecules, Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, China.
PMID: 35453416 DOI: 10.3390/antiox11040732
Abstract

Histone deacetylase 6 (HDAC6) acts as a regulator of the nuclear factor kappa-B (NF-κB) signaling pathway by deacetylating the non-histone protein myeloid differentiation primary response 88 (MyD88) at lysine residues, which is an adapter protein for the Toll-like Receptor (TLR) and interleukin (IL)-1β receptor. Over-activated immune responses, induced by infiltrated immune cells, excessively trigger the NF-κB signaling pathway in other effector cells and contribute to the development of rheumatoid arthritis (RA). It has also been reported that HDAC6 can promote the activation of the NF-κB signaling pathway. In the present study, we showed that HDAC6 protein level was increased in the synovium tissues of adjuvant-induced arthritis rats. In addition, hydrogen sulfide (H2S) donor S-propargyl-cysteine (SPRC) can inhibit HDAC6 expression and alleviate inflammatory response in vivo. In vitro study revealed that HDAC6 overexpression activated the NF-κB signaling pathway by deacetylating MyD88. Meanwhile, sodium hydrosulfide (NaHS) or HDAC6 Inhibitor tubastatin A (tubA) suppressed the pro-inflammatory function of HDAC6. Furthermore, the reduced expression of HDAC6 appeared to result from transcriptional inhibition by S-sulfhydrating specificity protein 1 (Sp1), which is a transcription factor of HDAC6. Our results demonstrate that Sp1 can regulate HDAC6 expression, and S-sulfhydration of Sp1 by antioxidant molecular H2S ameliorates RA progression via the HDAC6/MyD88/NF-κB signaling pathway.

Keywords

H2S; HDAC6; Sp1; rheumatoid arthritis.

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