Overactivation of Mitogen-Activated Protein Kinase and Suppression of Mitofusin-2 Expression Are Two Independent Events in High Mobility Group Box 1 Protein–Mediated T Cell Immune Dysfunction

Abstract

High mobility group box 1 protein (HMGB1), a critical proinflammatory cytokine, has recently been identified to be an immunostimulatory signal involved in sepsis-related immune dysfunction when released extracellularly, but the potential mechanism involved remains elusive. Here, we showed that the treatment with HMGB1 in vitro inhibited T lymphocyte immune response and expression of mitofusin-2 (Mfn-2; a member of the mitofusin family) in a dose-and time-dependent manner. Upregulation of Mfn-2 expression attenuated the suppressive effect of HMGB1 on T cell immune function. The phosphorylation of both extracellular signal-regulated kinase (ERK)1/2 and p38 mitogen-activated protein kinase (MAPK) was markedly upregulated by treating with high amount of HMGB1, while pretreatment with ERK1/2 and p38 MAPK-specific inhibitors (U0126 and SB203580) could attenuate suppression of T cell immune function and nuclear factor of activated T cell (NFAT) activation induced by HMGB1, respectively. HMGB1-induced activity of ERK1/2 and p38 was not fully inhibited in the presence of U0126 or SB203580. Interestingly, overexpression of Mfn-2 had no marked effect on HMGB1-mediated activation of MAPK, but could attenuate the suppressive effect of HMGB1 on the activity of NFAT. Thus, the mechanisms involved in HMGB1-induced T cell immune dysfunction in vitro at least partly include suppression of Mfn-2 expression, overactivation of ERK1/2, p38 MAPK, and intervention of NFAT activation, while the protective effect of Mfn-2 on T cell immune dysfunction induced by HMGB1 is dependent on other signaling pathway associated with NFAT, but not MAPK. Taken together, we conclude that overactivation of MAPK and suppression of Mfn-2 expression are two independent events in HMGB1-mediated T cell immune dysfunction.

Nuclear Factor of Activated T Cells Regulates Neutrophil Recruitment, Systemic Inflammation, and T-Cell Dysfunction in Abdominal Sepsis

“…IL-6 has previously been described as an NFAT target gene (25,50), but the finding that NFAT regulates HMGB1 is new. High levels of HMGB1 have recently been shown to prevent NFAT activation in T cells (51,52), suggesting that it may act as an endogenous negative regulator of NFAT in sepsis in an attempt to limit the damage. Similar examples of endogenous regulators of calcineurin/NFAT have been demonstrated in the past, such as DSCR1 (53).…”

The Endoplasmic Reticulum Stress Response in Neuroprogressive Diseases: Emerging Pathophysiological Role and Translational Implications

“…In this context, it is of paramount importance that the activity of this enzyme may be inhibited in an environment of chronic inflammation and nitrosative stress. For example, MAPK upregulation suppresses Mfn2 activity [ 261 ] and there is some evidence that this enzyme is inhibited in an environment in which the production of pro-inflammatory mediators is elevated [ 257 ]. It is also of interest that the capacity of Mfn2 to stimulate mitochondrial function is dependent on the activation of the PI3K/Akt pathway.…”

The Effect and Regulatory Mechanism of High Mobility Group Box-1 Protein on Immune Cells in Inflammatory Diseases

“…HMGB1 can directly evoke the differentiation of Th17 and Th2 cells, through which the protein promotes mucus production and airway inflammation in asthmatic mice [ 148 ]. After injury, release of HMGB1 immunosuppresses T lymphocytes [ 151 , 152 ] and we found that stimulation with HMGB1 can induce late apoptosis and necrosis as well as mitochondrial apoptosis in T cells [ 151 ]. We also found that antibody neutralization of HMGB1 promoted the T cell-dependent immune response in septic rats, thereby ameliorating multiple organ damage [ 153 , 154 ].…”