key: cord-0977769-pfp7p1jx
authors: Colavita, Laura; Ciprandi, Giorgio; Salpietro, Annamaria; Cuppari, Caterina
title: HMGB1: A pleiotropic activity
date: 2020-11-24
journal: Pediatr Allergy Immunol
DOI: 10.1111/pai.13358
sha: 687902bec1279075af05146a85bbaf926e9b6d15
doc_id: 977769
cord_uid: pfp7p1jx

High‐mobility group box 1 (HMGB1) is a nuclear protein involved in DNA replication, transcription, recombination, and repair. In the extracellular space, the HMGB1 plays an essential role in the onset and perpetuation of inflammation, belonging to the group of damage‐associated molecular pattern (DAMP) molecules, also called alarmins. For this, HMGB1 has been studied in several acute and chronic inflammatory diseases as an early biomarker of inflammation. An increased concentration of HMGB1 has been detected in serum, as the expression of systemic inflammation, and in specific samples (such as stool, synovial fluid, nasal lavage fluid, sputum, and cerebrospinal fluid), as the expression of local production, in several infectious and/or inflammatory diseases. These data are particularly important because they open new futuristic possibilities for target therapies, potentially also for the COVID‐19 treatment.

petuation of inflammation in response to infectious or sterile stimuli that may cause cell injury or death. 2 The release of HMGB1 in the extracellular space may be a consequence of cellular necrosis or active secretion from more types of immune cells (such as monocytes, macrophages, endothelial cells, enterocytes, pituicytes, dendritic cells, and natural killer cells) in response to infectious agents and/or inflammatory cytokines. PAMPs (pathogen-associated molecular patterns), lipopolysaccharide, TNF-α (tumor necrosis factor-α), and IL-1 (interleukin-1) strongly stimulate the release of HMGB1 from immune cells. Type 1 and type 2 interferons induce intracellular localization of HMGB1 instead. In the extracellular space, the HMGB1 binds membrane receptors RAGE (receptor for advanced glycation end products) or TLRs (Toll-like receptors) such as TLR-2 and TLR-4. The activation of intracellular signaling cascade through TRAF6, NEMO, and IKK IKBα causes the induction of the transcription factor NF-kB (nuclear factor kappalight-chain-enhancer of activated B cells). This causes the production and secretion of various pro-inflammatory cytokines (IL-12, IL-6, IL-1, IL-8, and TNF-α) and the amplification of the inflammation. 1-3

The central role of HMGB1 in the onset and perpetuation of inflammation makes this cytokine a possible early marker for various In epilepsy and febrile seizures, the HMGB1 plays an important pathogenetic role, with consequent possible creation of a novel antiepileptic strategy based on pharmacological modulation of HMGB1-TLR/RAGE axis. HMGB1 is an essential mediator of the neuroinflammation, and its role has been hypothesized in autism spectrum disorders. [3] [4] [5] [6] In some diseases, such as heart infarction, traumatic brain injury, pulmonary fibrosis, and acute lung injury, HMGB1 is passively released by damaged cells, and, for this, it may be considered the expression of cell necrosis degree in the early phases. In the extracellular space, 

The peer review history for this article is available at https://publo ns.com/publo n/10.1111/pai.13358. 

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