HMGB1 released from nociceptors mediates inflammation

Huan Yang*, Qiong Zeng, Harold A. Silverman, Manojkumar Gunasekaran, Sam J. George, Alex Devarajan, Meghan E. Addorisio, Jianhua Li, Téa Tsaava, Vivek Shah, Timothy R. Billiar, Haichao Wang, Michael Brines, Ulf Andersson, Valentin A. Pavlov, Eric H. Chang, Sangeeta S. Chavan*, Kevin J. Tracey*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

37 Scopus citations


Inflammation, the body's primary defensive response system to injury and infection, is triggered by molecular signatures of microbes and tissue injury. These molecules also stimulate specialized sensory neurons, termed nociceptors. Activation of nociceptors mediates inflammation through antidromic release of neuropeptides into infected or injured tissue, producing neurogenic inflammation. Because HMGB1 is an important inflammatory mediator that is synthesized by neurons, we reasoned nociceptor release of HMGB1 might be a component of the neuroinflammatory response. In support of this possibility, we show here that transgenic nociceptors expressing channelrhodopsin-2 (ChR2) directly release HMGB1 in response to light stimulation. Additionally, HMGB1 expression in neurons was silenced by crossing synapsin-Cre (Syn-Cre) mice with floxed HMGB1 mice (HMGB1f/f). When these mice undergo sciatic nerve injury to activate neurogenic inflammation, they are protected from the development of cutaneous inflammation and allodynia as compared to wild-type controls. Syn-Cre/HMGB1fl/fl mice subjected to experimental collagen antibody-induced arthritis, a disease model in which nociceptor-dependent inflammation plays a significant pathological role, are protected from the development of allodynia and joint inflammation. Thus, nociceptor HMGB1 is required to mediate pain and inflammation during sciatic nerve injury and collagen antibody-induced arthritis.

Original languageEnglish
Article numbere2102034118
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number33
StatePublished - 17 Aug 2021
Externally publishedYes


  • Arthritis
  • Cytokine
  • DAMP
  • HMGB1
  • Sciatic nerve injury


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