Article

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: 2.2). 07/2012; 76(5):483-90. DOI: 10.1111/j.1365-3083.2012.02759.x
Source: PubMed

ABSTRACT 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.

2 Bookmarks
 · 
155 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Autoimmune diseases are immune disorders characterized by T cell hyperactivity and B cell overstimulation leading to overproduction of autoantibodies. Although the pathogenesis of various autoimmune diseases remains to be elucidated, environmental factors have been thought to contribute to the initiation and maintenance of auto-respond inflammation. Toll-like receptors (TLRs) are pattern recognition receptors belonging to innate immunity that recognize and defend invading microorganisms. Besides these exogenous pathogen-associated molecular patterns, TLRs can also bind with damage-associated molecular patterns produced under strike or by tissue damage or cells apoptosis. It is believed that TLRs build a bridge between innate immunity and autoimmunity. There are five adaptors to TLRs including MyD88, TRIF, TIRAP/MAL, TRAM, and SARM. Upon activation, TLRs recruit specific adaptors to initiate the downstream signaling pathways leading to the production of inflammatory cytokines and chemokines. Under certain circumstances, ligation of TLRs drives to aberrant activation and unrestricted inflammatory responses, thereby contributing to the perpetuation of inflammation in autoimmune diseases. In the past, most studies focused on the intracellular TLRs, such as TLR3, TLR7, and TLR9, but recent studies reveal that cell surface TLRs, especially TLR2 and TLR4, also play an essential role in the development of autoimmune diseases and afford multiple therapeutic targets. In this review, we summarized the biological characteristics, signaling mechanisms of TLR2/4, the negative regulators of TLR2/4 pathway, and the pivotal function of TLR2/4 in the pathogenesis of autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, Sjogren's syndrome, psoriasis, multiple sclerosis, and autoimmune diabetes.
    Clinical Reviews in Allergy & Immunology 12/2013; · 5.59 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: High-mobility group box 1 (HMGB1) proteins are substantially up-regulated in acute and chronic hepatitis. However, the immunopathogenic role of HMGB1 in patients with chronic hepatitis B (CHB) has not been elucidated. In this study, using a cohort of 36 CHB patients, we demonstrated a crucial role for HMGB1 to modulate balance between regulatory T (Treg) and T helper 17 (Th17) cells via the toll-like receptor (TLR)-4-interleukin (IL)-6 pathway. Serum HMGB1 levels were dramatically higher in CHB patients and increased along with liver injury, inflammation and fibrosis. Notably, HMGB1 increased along with decreased Treg/Th17 cells ratios in the periphery or intrahepatic microenvironment, which provides a clue for HMGB1 to favour Th17 responses whereas inhibit Treg responses. For in vitro studies, serum pools were constructed with serum from CHB patients at an advanced stage, whereas peripheral blood mononuclear cells (PBMC) pools were constructed with cells from those at an early stage. CHB-serum significantly enhanced retinoic acid-related orphan receptor-γt (RORγt), whereas they inhibited forkhead box P3 (Foxp3) expression in CHB-PBMC, which could be reversed by blocking of HMGB1, TLR4, or IL-6. Besides, recombinant HMGB1 (rHMGB1) dose-dependently up-regulated RORγt whereas down-regulated Foxp3 expression in CHB-PBMC, and meanwhile, rHMGB1 enhanced TLR4 and IL-6 expression in CHB-PBMC. Moreover, the axis of HMGB1-TLR4-IL-6-Treg/Th17 required noncontact interactions between CD4 and non-CD4 cells. In addition, rHMGB1 down-regulated anti-inflammatory proteins on CD4(+) CD25(+) cells whereas up-regulated pro-inflammatory cytokines in CD4(+) CD25(-) cells. In summary, enriched HMGB1 in CHB patients shifts Treg/Th17 balance to Th17 dominance via the TLR4-IL-6 pathway, which exacerbates liver injury and inflammation.
    Journal of Viral Hepatitis 02/2014; 21(2):129-40. · 3.08 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    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 01/2014; 2014:257930. · 3.88 Impact Factor

Full-text

View
26 Downloads
Available from
May 22, 2014