4.8 Article

HMGB1 released from nociceptors mediates inflammation

Publisher

NATL ACAD SCIENCES
DOI: 10.1073/pnas.2102034118

Keywords

HMGB1; cytokine; arthritis; DAMP; sciatic nerve injury

Funding

  1. NIH: National Institute of General Medical Services (NIGMS) [R35GM118182]
  2. NIGMS [R01GM132672, 1R01GM128008-01, R01GM063075]
  3. National Institute of Allergy and Infectious Diseases [P01AI102852]
  4. National Center of Complementary and Integrative Health [R01AT005076]

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Inflammation is initiated by molecular signatures of microbes and tissue injury, triggering the body's defensive response. Neuronal synthesis of HMGB1 is an important mediator of inflammation, with the release of HMGB1 by nociceptors playing a role in neurogenic inflammation.
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.

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