N4-acetylcytidine is required for sustained NLRP3 inflammasome activation via HMGB1 pathway in microglia

  • Cell Signal. 2019 Jun;58:44-52. doi: 10.1016/j.cellsig.2019.03.007.
JuanJuan Duan  1 ,  Qifang Zhang  2 ,  Xiaohong Hu  3 ,  Deqin Lu  4 ,  Wenfeng Yu  5 ,  Hua Bai  6
Affiliations
  • 1. Department of Neurology, the Third Affiliated Hospital of Guizhou Medical University, Duyun 558000, China; Department of Neurology, the Affiliated Hospital of Guizhou Medical University, Guiyang 550004, China.
  • 2. Key Laboratory of Endemic and Ethnic Diseases, Ministry of Education, Guizhou Medical University, Guiyang 550004, China; Key Laboratory of Medical Molecular Biology, Guizhou Medical University, Guiyang 550004, China. Electronic address: [email protected].
  • 3. Key Laboratory of Endemic and Ethnic Diseases, Ministry of Education, Guizhou Medical University, Guiyang 550004, China; Key Laboratory of Medical Molecular Biology, Guizhou Medical University, Guiyang 550004, China.
  • 4. Department of Pathology, Guizhou Medical University, Guiyang 550004, China.
  • 5. Key Laboratory of Endemic and Ethnic Diseases, Ministry of Education, Guizhou Medical University, Guiyang 550004, China; Key Laboratory of Medical Molecular Biology, Guizhou Medical University, Guiyang 550004, China. Electronic address: [email protected].
  • 6. Department of Neurology, the Third Affiliated Hospital of Guizhou Medical University, Duyun 558000, China; Medical Laboratory Center, Third Affiliated Hospital of Guizhou Medical University, Duyun 558000, China; Department of Neurology, the Affiliated Hospital of Guizhou Medical University, Guiyang 550004, China. Electronic address: [email protected].
PMID: 30853521 DOI: 10.1016/j.cellsig.2019.03.007
Abstract

Persistent inflammasome activation contributes to chronic, low grade inflammation. However, it is unclear how the inflammasome activation is sustained after initiation. Here we reported that N4-acetylcytidine (N4A), a nucleoside metabolite, activated microglia and sustained NLRP3 inflammasome activation by inducing HMGB1 signaling. Released HMGB1 through N4A activated NFκB and induced NLRP3 expression. HMGB1 silencing abolished N4A-stimulated NFκB activation, NLRP3 and persistent HMGB1 expression. In addition, inhibiting NLRP3 expression by RNAi abrogated N4A-mediated HMGB1 expression. Lack of NLRP3 inflammasome adaptor named apoptosis-associated speck-like protein containing a CARD (ASC) abrogated N4A-induced HMGB1 expression, NFκB activation, and NLRP3 expression. Taken together, our results reveal a novel role of N4A in activation of NLRP3 inflamasome via HMGB1 feedback.

Keywords
HMGB1; Microglia; N(4)-acetylcytidine (N4A); NFκB; NLRP3 inflammasome.
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