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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    • "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.
    Mediators of Inflammation 05/2014; 2014:257930. DOI:10.1155/2014/257930 · 3.24 Impact Factor
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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.
    Frontiers in Immunology 03/2013; 4:68. DOI:10.3389/fimmu.2013.00068
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    ABSTRACT: Objectives: Macrophages are central to the inflammatory processes driving rheumatoid arthritis (RA) synovitis. The molecular pathways that are induced in synovial macrophages and thereby promote RA disease pathology remain poorly understood. Methods: We used microarray to characterise the transcriptome of synovial fluid (SF) macrophages compared with matched peripheral blood monocytes from patients with RA (n=8). Results: Using in silico pathway mapping, we found that pathways downstream of the cholesterol activated liver X receptors (LXRs) and those associated with Toll-like receptor (TLR) signalling were upregulated in SF macrophages. Macrophage differentiation and tumour necrosis factor α promoted the expression of LXRα. Furthermore, in functional studies we demonstrated that activation of LXRs significantly augmented TLR-driven cytokine and chemokine secretion. Conclusions: The LXR pathway is the most upregulated pathway in RA synovial macrophages and activation of LXRs by ligands present within SF augments TLR-driven cytokine secretion. Since the natural agonists of LXRs arise from cholesterol metabolism, this provides a novel mechanism that can promote RA synovitis.
    Annals of the rheumatic diseases 02/2013; 72(12). DOI:10.1136/annrheumdis-2012-202872 · 10.38 Impact Factor
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