Anti-HMGB1 Neutralizing Antibody Ameliorates Neutrophilic Airway Inflammation by Suppressing Dendritic Cell-Mediated Th17 Polarization

Abstract

We demonstrate that high mobility group box 1 protein (HMGB1) directs Th17 skewing by regulating dendritic cell (DC) function. First, our in vitro studies reveal that recombinant HMGB1 (rHMGB1) activates myeloid DCs to produce IL-23 in vitro, and rHMGB1-activated DCs prime naïve lymphocytes to produce the Th17 cytokine IL-17A. Second, we demonstrate that anti-HMGB1 neutralizing antibody attenuates HMGB1 expression, neutrophilic inflammation, airway hyperresponsiveness, and Th17-related cytokine secretion in vivo by using a murine model of neutrophilic asthma induced by ovalbumin (OVA) plus lipopolysaccharide (LPS). Furthermore, anti-HMGB1 neutralizing antibody decreases the number of Th17 cells in lung cells and suppresses the production of IL-23 by lung CD11C+ APCs. Finally, we show that intranasal adoptive transfer of rHMGB1-activated DCs was sufficient to restore lung neutrophilic inflammation and the Th17 response in a DC-driven model of asthma, whereas the transfer of rHMGB1 plus anti-HMGB1-treated mDCs significantly reduced these inflammation phenotypes. These data suggest, for the first time, that HMGB1 drives the DC-polarized Th17-type response in allergic lung inflammation and that blocking HMGB1 may benefit the attenuation of neutrophilic airway inflammation in asthma.

High-Mobility Group Box 1: A Novel Target for Treatment of Pseudomonas aeruginosa Keratitis

“…In addition to regulation of monocytic populations of cells, in allergic lung inflammation (42) recent data suggest that HMGB1 directs Th17 skewing by regulating dendritic cell function, suggesting that HMGB1 drives the DC-polarized Th17-type response and that blocking HMGB1 may be beneficial in attenuating neutrophilic airway inflammation in asthma via this mechanism. The latter was not investigated in the current study reported herein, but suggests another possible indirect role for HMGB1 in recruitment of PMN during bacterial keratitis.…”

Cationic polyaspartamide-based nanocomplexes mediate siRNA entry and down-regulation of the pro-inflammatory mediator high mobility group box 1 in airway epithelial cells

“…HMGB1 can modulate the inflammatory response in the airway diseases by inducing MUC8 expression in airway epithelial cells (Kim et al, 2012) and mediating cytokine production via Toll-like receptor 4 in acute lung injury (Deng et al, 2013). Moreover, HMGB1 protein was shown to be an important mediator in asthma since its inhibition by neutralizing antibodies lowered many inflammatory responses in mice lung (Zhang et al, 2014). Thus, HMGB1 may be a desirable target to be down-regulated in asthma and other respiratory diseases.…”

“…Interestingly, the concentrations of HMGB1 in asthmatic and COPD (chronic obstructive pulmonary disease) patients positively and significantly correlated with neutrophils counts and percentage of neutrophils in sputum (Hou et al, 2011). In another study, it has been demonstrated that HMGB1 neutralizing antibody attenuates neutrophilic inflammation in vivo by using a murine model of neutrophilic asthma induced by ovalbumin plus lipopolysaccharide (Zhang et al, 2014). However, the role of HMGB1 in respiratory diseases is still elusive but nevertheless these studies suggest an involvement of this cytokine in their pathogenesis.…”

2-O, 3-O Desulfated Heparin Blocks High Mobility Group Box 1 Release by Inhibition of p300 Acetyltransferase Activity

“…HMGB1 ligation of RAGE, TLR-2, or TLR-4 results in the activation of nuclear factor-kB and neutrophilic inflammation (10). HMGB1 also contributes to chronic neutrophilic inflammatory airway disease by blunting macrophage phagocytosis and clearance of bacteria (11), inhibiting phagocytosis of apoptotic neutrophils (12), promoting neutrophil extracellular trap formation (13), and inducing dendritic cell-mediated Th17 polarization (14). Although HMGB1 is a potential therapeutic target for reducing excessive inflammation in chronic airway diseases, there are currently no therapies that target HMGB1 inhibition.…”