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

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.

HMGB1 is an early and critical mediator in an animal model of uveitis induced by IRBP-specific T cells

“…Suppression of Th17 cell expansion and attenuation of the disease by HMGB1 blockade were also observed in experimental autoimmune myocarditis [46]. HMGB1 promotes the differentiation of Th17 via up-regulating TLR2 and IL-23 of CD14ϩ monocytes from patients with rheumatoid arthritis [47]. In the human, however, HMGB1 directly enhances immune-inhibitory functions of Tregs via RAGE-mediated mechanisms and limits the number and activity of conventional T cells [48].…”

Alarmins and Antitumor Immunity

“…60,66,67 Aside from promoting adaptive immune responses, HMGB1 has been shown to contribute to inflammation, such as during endotoxic shock, 4,64,68 trauma-induced inflammation, 69 and autoimmune disorders. [70][71][72][73] HMGN1 is composed of 2 major domains, a C-terminal chromatin-unfolding domain and an N-terminal nucleosomal binding domain, and is highly expressed in the nucleoli of proliferative tissues that undergo constant turnover, such as epithelial and stem cells. 52 Like HMGB1, HMGN1 has critical biological functions in development, host defense and tissue repair.…”

Emerging Role of High Mobility Group Box-1 in Thrombosis-Related Diseases

“…Once in the extracellular space, HMGB-1 exerts its biological functions via interaction with its receptors, including receptor for advanced glycation end products (RAGE) [21,22], TLR2 [23][24][25][26], TLR4 [27][28][29][30], and TLR9 [31]. The interaction between HMGB-1 and its receptors has been shown to induce cell adhesion [32], permeability [33,34], chemotaxis [35], inflammation [36][37][38], autophagy [39][40][41], apoptosis [42][43][44], thrombosis [16,45,46], angiogenesis [47,48], fibrosis [49,50], and epithelialmesenchymal transition (EMT) [51,52].…”