HMGB1 Promotes the Differentiation of Th17 via Up-Regulating TLR2 and IL-23 of CD14+ Monocytes from Patients with Rheumatoid Arthritis

Department of Immunology, Institute of Laboratory Medicine, Jiangsu University, Zhenjiang, China Department of Laboratory Medicine, Henan Provincial Hospital of Traditional Chinese Medicine, Zhengzhou, China The Central Laboratory, Department of Laboratory Medicine, Affiliated Hospital of Jiangsu University, Zhenjiang, China.
Scandinavian Journal of Immunology (Impact Factor: 1.74). 07/2012; 76(5):483-90. DOI: 10.1111/j.1365-3083.2012.02759.x
Source: PubMed


High-mobility group box 1 (HMGB1) is a non-histone nuclear protein that is released extracellulary and has been implicated in autoimmune disease. Toll-like receptor 2 (TLR2) signalling is thought to be essential for the inflammatory response and for immune disorders. In recent studies, enhanced HMGB1 and TLR2 expressions have been found in rheumatoid arthritis (RA), respectively. The aim of this study is to explore whether HMGB1 stimulation can up-regulate the expression of TLR2 on CD14(+) monocytes from patients with RA and to clarify the subsequent events involving Th17 cells and Th17 cell-associated cytokine changes. Our results showed that the frequency of CD14(+) cells in peripheral blood mononuclear cell (PBMC) was obviously increased, and enhanced expression of TLR2 on CD14(+) monocytes was also found in patients with RA, compared with healthy controls with statistical significance (P < 0.001). In addition, the levels of IL-17, IL-23 and IL-6 in supernatants from cultured monocytes from patients and in patient's plasma were increased, and NF-κB, the downstream target of TLR2, also showed a marked elevation after monocytes were stimulated by HMGB1. This implies that the enhanced TLR2 pathway and Th17 cell polarization may be due to HMGB1 stimulation in rheumatoid arthritis.

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Available from: Siamak Sandoghchian, Dec 23, 2013
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    • "Li Y. et al. found that HMGB1 can bind to Gadd45a, which may contribute to DNA demethylation of CD11a and CD70 in SLE CD4 + T cells [17]. Enhanced HMGB1 is reported to inhibit Treg and promote Th17 response during the immune and inflammatory process [18] [19] [20]. In the study, we investigated whether HMGB1 is involved in the regulation of abnormal expression of STAT3 in CD4 + T cells from aGVHD patients. "
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    ABSTRACT: Treg/Th17 balance plays a critical role in maintaining immune homeostasis of acute graft-versus-host disease (aGVHD) patients. STAT3 is an important factor involved in the instability of Treg and the promotion of Th17. HMGB1 is a cytokine mediator of inflammation and an important chromatin protein regulating gene transcription. In this study, we found that the expression of HMGB1 and STAT3 were higher in CD4(+) T cells of patients with aGVHD compared with those without aGVHD, and the HMGB1 expression was positively correlated with the STAT3 expression. Simultaneously, their expressions were positively correlated with the severity of the aGVHD. We also demonstrated that HMGB1 could regulate the expression of STAT3 by modulation of its DNA methylation in CD4(+) T cells, moreover downregulated HMGB1 in aGVHD CD4(+) T cells could change the ratio of Treg/Th17. These data strongly suggest that HMGB1 plays a crucial role in regulation of Treg/Th17 and progression of aGVHD. Copyright © 2015. Published by Elsevier Inc.
    Full-text · Article · Aug 2015 · Clinical Immunology
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    • "High mobility group box 1 (HMGB1) is a DNA-binding, nuclear protein that can act as an alarmin, which is a danger signal that alerts the innate immune system to initiate the host defense [11]. Some studies demonstrate that HMGB1 stimulates DCs to induce the production of Th17 polarization-related factors in vitro and promotes the Th17 response in acute allograft rejection [12], experimental autoimmune myocarditis [13], and rheumatoid arthritis [14]. In our recent studies, an increase in HMGB1 expression and Th17-mediated (or Th17-involved) airway inflammation have been found in a murine model of neutrophilic asthma, and HMGB1 expression in lung tissue was positively correlated with the IL-17 level or neutrophil numbers in bronchoalveolar lavage fluid (BALF) [15]. "
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    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.
    Full-text · Article · May 2014 · Mediators of Inflammation
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    • "Furthermore, HMGB1 elicits increased suppressive capacity of Treg when co-cultured with effector T-cells in a RAGE-dependent fashion. Additionally, several reports provide evidence suggesting that HMGB1 may contribute to Th17 cells proliferation and activation in the context of autoimmune disease, including rheumatoid arthritis, myocarditis, as well as acute allograft rejection (Duan et al., 2011; Su et al., 2011; He et al., 2012b; Shi et al., 2012). "
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    ABSTRACT: High-mobility group box 1 (HMGB1) is a leaderless cytokine, like the IL-1 and FGF family members, that has primary roles within the nucleus and the cytosol. Within the nucleus, it serves as another guardian of the genome, protecting it from oxidant injury and promoting access to transcriptional complexes such as nuclear hormone/nuclear hormone receptors and p53/p73 complexes. Within the cytosol it promotes autophagy and recruitment of the myddosome to Toll-like receptor (TLR) 9 vesicular compartments. Outside of the cell, it can either bind to specific receptors itself, or with high affinity to DNA, nucleosomes, IL-1β, lipopolysaccharide, and lipoteichoic acid to mediate responses in specific physiological or pathological conditions. Currently identified receptors include TLR2, TLR4, the receptor for advanced glycation end products, CD24-Siglec G/10, chemokine CXC receptor 4, and TIM-3. In terms of its effects or functions within lymphoid cells, HMGB1 is principally secreted from mature dendritic cells (DCs) to promote T-cell and B-cell reactivity and expansion and from activated natural killer cells to promote DC maturation during the afferent immune response. Some studies suggest that its primary role in the setting of chronic inflammation is to promote immunosuppression. As such, HMGB1 is a central cytokine for all lymphoid cells playing a role complementary to its better studied role in myeloid cells.
    Full-text · Article · Mar 2013 · Frontiers in Immunology
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