Neurons Are a Primary Driver of Inflammation via Release of HMGB1

Abstract

Recent data show that activation of nociceptive (sensory) nerves turns on localized inflammation within the innervated area in a retrograde manner (antidromically), even in the absence of tissue injury or molecular markers of foreign invaders. This neuroinflammatory process is activated and sustained by the release of neuronal products, such as neuropeptides, with the subsequent amplification via recruitment of immunocompetent cells, including macrophages and lymphocytes. High mobility group box 1 protein (HMGB1) is a highly conserved, well characterized damage-associated molecular pattern molecule expressed by many cells, including nociceptors and is a marker of inflammatory diseases. In this review, we summarize recent evidence showing that neuronal HMGB1 is required for the development of neuroinflammation, as knock out limited to neurons or its neutralization via antibodies ameliorate injury in models of nerve injury and of arthritis. Further, the results of study show that HMGB1 is actively released during neuronal depolarization and thus plays a previously unrecognized key etiologic role in the initiation and amplification of neuroinflammation. Direct targeting of HMGB1 is a promising approach for novel anti-inflammatory therapy.

The Cellular Senescence Factor Extracellular HMGB1 Directly Inhibits Oligodendrocyte Progenitor Cell Differentiation and Impairs CNS Remyelination

“…Blocking extracellular HMGB1 significantly lessens disease severity by attenuating T cell extravasation into the CNS (Robinson et al, 2013 ). Interestingly, HMGB1 is also a well-known mediator of inflammation (Gorgulho et al, 2019 ; Wang et al, 2019 ; Ciprandi et al, 2020 ; Liu et al, 2020 ; Nishibori et al, 2020 ; Yang et al, 2021 ). We had analyzed the degree of activated microglia/macrophages in HMGB1-LPC and control-LPC lesioned animals as a means to discern whether the impaired recovery in the HMGB1-treated animals was also reflective of an ongoing, active lesion.…”

“…Patients with cerebral and myocardial ischemia have also been found to have elevated levels of HMGB1 in their blood serum (Goldstein et al, 2006 ), much in the same way MS patients have elevated blood serum levels of HMGB1 (Bucova et al, 2020 ). HMGB1 has also been implicated in the periphery, with its release from neurons linked to localized inflammation in animal models of nerve injury and arthritis (Yang et al, 2021 ). Furthermore, we have studied HMGB1 in the context of MS on account of its excessive expression and production of HMGB1 from progenitor cells which exhibit a cellular senescent phenotype (Davalos et al, 2013 ; Nicaise et al, 2019 ).…”

Complement System and Alarmin HMGB1 Crosstalk: For Better or Worse

“…Extracellular HMGB1 is therefore recognized as one of the DAMPs which act as major mediators in immunity ( 26 ). Indeed, HMGB1 may be passively released from damaged tissues, late-apoptotic and necrotic cells, as well as actively produced (through a non-canonical secretion pathway) by activated immune cells or even by neurons, as part of inflammatory processes ( 27 – 29 ). In contrast to the immediate activation of the complement system, the secretion of HMGB1 is often delayed, hours after the initial stimulation ( 23 , 30 ), and its level often remains elevated days after in contexts of chronic inflammation associated with auto-immunity, infection and cancer.…”

Role of high mobility group box protein 1 in depression: A mechanistic and therapeutic perspective

“…HMGB1 is considered as an essential neuroinflammatory facilitator, which is released by glial cells and neurons upon inflammasome activation and acts as a pro-inflammatory cytokine[ 15 ]. Neurons are considered as a primary and necessary driver of neuroinflammation through release of HMGB1, with the subsequent amplification via recruitment of immunocompetent cells, including microglia and astrocytes[ 31 ]. HMGB1 has been proved that it releases from neurons in many central nervous system (CNS) diseases and then triggeres neuroinflammation as an upstream inflammatory mediator[ 15 , 32 ].…”