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• HMGB1 is a non-histone DNA-binding nuclear protein. • HMGB1 can actively secreted in the form of intracellular vesicles. • HMGB1 can also be released from necrotic cells or injured cells passively. • After binding with its receptors, HMGB1 trigger a series of biological effects. • HMGB1 was involved in the occurrence and development of asthma. High-mobility group box protein 1 (HMGB1) is a non-histone deoxyribonucleic acid-binding nuclear protein. In physiological state it is involved in gene transctioripn regulation and cell replication, differentiation and maturation. HMGB1 is actively secreted into the extracellular space in the form of intracellular vesicles, upon stimulation of inflammation and infection, by monocytes, macrophages, dendritic cells (DCs), and other immune cells, and can also be passively released by necrotic or injured cells. After binding with the corresponding receptors, HMGB1 can activate the downstream substrate and trigger a series of biological effects. HMGB1 was mainly dependent on toll-like re ceptors (TLR) 2 and 4, and receptors for advanced glycation end products (RAGE) to trigger intracellular signal transduction, and mediate innate and adoptive immune responses. Besides these, studies have reported the participation of TLR3, TLR9, T-cell immunoglobulin mucin (TIM) 3, CD24, anti-N-methyl-D-aspartate receptor (NMDAR) in Th2 inflammatory response, eosinophilic airway inflammation, and airway hyperresponsiveness, mediated by HMGB1 in asthma. Both clinical and experimental studies suggested that HMGB1 was involved in the pathogenesis of asthma probably by regulating the downstream signaling pathways via corresponding receptors. This article reviews the role of HMGB1 in pathogenesis of asthma, and provides a new theoretical basis for the diagnosis and treatment of asthma. [ABSTRACT FROM AUTHOR]

The Th (T helper) 2 response is characteristic of allergic asthma, and Th17 cells are involved in more severe asthma. Recent studies demonstrated that HMGB1 (High mobility group box 1 protein) regulates airway inflammation and the Th2, Th17 inflammatory response in asthma. HMGB1 can interact with Toll-like receptors (TLR) 2 and 4, and the receptor for advanced glycation end products (RAGE), activating the NF-κB (nuclear factor kappa B) signaling pathway and inducing the release of downstream inflammatory mediators. Both Th cells and dendritic cells express TLR2, TLR4, and RAGE receptors. Therefore, we speculate that HMGB1 could regulate the differentiation of Th2, Th17 cells in asthma through direct and indirect mechanisms. An ovalbumin (OVA)-induced mouse asthmatic model was established. Anti-HMGB1 antibody or rHMGB1 was administered to OVA-sensitized mice 30 min prior to each challenge. For in vitro studies, magnetically separated CD4 + naive T cells were stimulated with or without rHMGB1 and/or anti-HMGB1 antibody. BMDCs (bone marrow-derived dendritic cells)-stimulated with or without rHMGB1 and/or anti-HMGB1 antibody were cocultured with CD4 + naive T cells. Our study showed that administration of rHMGB1 aggravated airway inflammation and mucus production, and induced Th2, Th17 polarization in asthmatic mice, and that anti-HMGB1 antibody weakened characteristic features of asthma and blocked the Th2, Th17 inflammatory responses. HMGB1 could directly act on naive T cells to induce differentiation of Th2, Th17 cells in vitro through activating the TLR2, TLR4, RAGE-NF-κB signal pathway in CD4 + naive T cells. HMGB1 could also indirectly promote Th2, Th17 differentiation via activating the TLR2, TLR4, RAGE-NF-κB signal pathway in DCs to mediate their maturation and antigen-presenting ability in vitro . [ABSTRACT FROM AUTHOR]

The ATP/P2X7 axis of dendritic cells (DCs) mediates the activation of NLRP3 inflammasome and promotes secretion of interleukin (IL)−1β and IL-18 to induce T helper (Th) 2, Th17 differentiation in the pathogenesis of asthma. NLRP3 inflammasome also regulates high mobility protein 1 (HMGB1) release in DCs. Recent studies demonstrated the correlation between HMGB1 expression and airway inflammation and hyper-responsiveness (AHR) in asthma. However, the relationship between the ATP/P2X7-NLRP3 axis and HMGB1 in DCs in asthma is still unclear. ATP, apyrase, Brilliant Blue G, BzATP, glibenclamide, and Z-YVAD-FMK were administered to ovalbumin (OVA)-induced murine asthmatic model. For in vitro studies, bone marrow-derived mononuclear cells (BMDCs) were primed with LPS and stimulated with the same reagents. Activation of the ATP/P2X7 axis aggravated airway inflammation and AHR in the lung and induced Th2, Th17 polarization in asthmatic mice. Inhibition of NLRP3 inflammasome weakened cardinal features of asthma and blocked Th2, Th17 polarization. In vitro and vivo, ATP/P2X7 axis activated NLRP3 inflammasome and induced HMGB1 expression and release from DCs. Inhibition of NLRP3 inflammasome reduced HMGB1 expression and release. The ATP/P2X7-NLRP3 axis of DCs participates in mediating airway inflammation, AHR, and promoting Th2, Th17 inflammatory responses in asthmatic mice by inducing HMGB1 expression and secretion. [ABSTRACT FROM AUTHOR]

• HMGB1 aggravates acute lung injury by suppressing immunosuppressive function of Tregs. • HMGB1 reduces the number and activity of Tregs. • HMGB1 reduces the secretion of anti-inflammatory cytokines (IL-10, TGF-β) from Tregs. • Tregs stimulated by HMGB1 regulate the macrophage polarization, as well as the proinflammatory response of macrophages. CD4+CD25+FoxP3+ T helper cells (Tregs), a subgroup of CD4+ T helper cells, are critical effectors that protect against acute lung injury (ALI) by contact-dependent suppression or releasing anti-inflammatory cytokines including interleukin-10 (IL-10), and transforming growth factor (TGF-β). HMGB1 (High mobility group box 1 protein) was identified as a nuclear non-histone DNA-binding chromosomal protein, which participates in the regulation of lung inflammatory response and pathological processes in ALI. Previous studies have suggested that Tregs overexpresses the HMGB1-recognizing receptor. However, the interaction of HMGB1 with Tregs in ALI is still unclear. To investigate whether HMGB1 aggravates ALI by suppressing immunosuppressive function of Tregs. Anti-HMGB1 antibody and recombinant mouse HMGB1 (rHMGB1) were administered in lipopolysaccharide (LPS)-induced ALI mice and polarized LPS-primed Tregs in vitro. The Tregs pre-stimulated with or without rHMGB1 were adoptively transferred to ALI mice and depleted by Diphtheria toxin (DT). For coculture experiment, isolated Tregs were first pre-stimulated with or without rHMGB1 or anti-HMGB1 antibody, then they were cocultured with bone marrow-derived macrophages (BMMs) under LPS stimulation. Tregs protected against acute lung pathological injury. HMGB1 modulated the suppressive function of Tregs as follows: reduction in the number of the cells and the activity of Tregs, the secretion of anti-inflammatory cytokines (IL-10, TGF-β) from Tregs, the production of IL-2 from CD4+ T cells and CD11c+ DCs, and the M2 polarization of macrophages, as well as inducing proinflammatory response of macrophages. HMGB1 could aggravate LPS induced-ALI through suppressing the activity and function of Tregs. [ABSTRACT FROM AUTHOR]

High-mobility group box 1 protein (HMGB1) is a crucial proinflammatory cytokine that contributes to acute lung injury (ALI). Macrophages are known to express the primary receptors (Toll-like receptor [TLR] 2, and TLR4) of HMGB1 for transmitting intracellular signals. Studies have revealed that double-stranded RNA activated protein kinase R (PKR), which is expressed in macrophages, participates in ALI by regulating macrophage polarization and proinflammatory cytokine release, and that PKR is normally activated by a subset of TLRs. The present study investigated whether HMGB1 engages in ALI by activating PKR in macrophages and inducing classically activated macrophage (M1) polarization via TLR2- and TLR4-mediated nuclear factor (NF)-κB signaling pathways. In an vivo mouse model of lipopolysaccharide (LPS)-induced ALI, anti-HMGB1, rHMGB1, LPS-RS (TLR2 and TLR4 antagonist), or C16 (PKR inhibitor) was administered to mice 2 h after LPS challenge or 1 h before LPS challenge. In vitro, bone marrow-derived macrophages from mice primed with LPS were stimulated with or without anti-HMGB1, rHMGB1, LPS-RS, or C16. Our studies revealed that rHMGB1 stimulation induced M1 polarization in ALI, and that anti-HMGB1 and C16 treatments had the opposite effect. Anti-HMGB1 and LPS-RS significantly inhibited LPS-induced PKR expression in macrophages; however, rHMGB1 administration increased PKR expression. These results indicate that HMGB1 participates in the pathogenesis of ALI by activating PKR in macrophages and inducing M1 polarization through TLR2- and TLR4-mediated NF-κB signaling pathways. • HMGB1 induces M1 polarization in LPS-induced ALI. • HMGB1 activates PKR in macrophages. • Inhibition of TLR2 and TLR4 weakens the activation of PKR in macrophages. • Inhibition of PKR attenuates M1 polarization. [ABSTRACT FROM AUTHOR]