3-bromopyruvate ameliorate autoimmune arthritis by modulating Th17/Treg cell differentiation and suppressing dendritic cell activation

Abstract

Recent studies have shown that cellular metabolism plays an important role in regulating immune cell functions. In immune cell differentiation, both interleukin-17-producing T (Th17) cells and dendritic cells (DCs) exhibit increased glycolysis through the upregulation of glycolytic enzymes, such as hexokinase-2 (HK2). Blocking glycolysis with 2-deoxyglucose was recently shown to inhibit Th17 cell differentiation while promoting regulatory T (Treg) cell generation. However, 2-DG inhibits all isoforms of HK. Thus, it is unclear which isoform has a critical role in Th17 cell differentiation and in rheumatoid arthritis (RA) pathogenesis. Here we demonstrated that 3-bromopyruvate (BrPA), a specific HK2 inhibitor, significantly decreased the arthritis scores and the histological scores in SKG mice, with a significant increase in Treg cells, decrease in Th17 cells, and decrease in activated DCs in the spleen. In vitro, BrPA facilitated the differentiation of Treg cells, suppressed Th17 cells, and inhibited the activation of DCs. These results suggested that BrPA may be a therapeutic target of murine arthritis. Although the role of IL-17 is not clarified in the treatment of RA, targeting cell metabolism to alter the immune cell functions might lead to a new therapeutic strategy for RA.

Lineage-Specific Metabolic Properties and Vulnerabilities of T Cells in the Demyelinating Central Nervous System

“…Indeed, we did observe severe side effects when we administered 3-BrPa systemically in EAE (mortality and hypothermia), suggesting that 3-BrPa would not be a proper choice of drug to treat MS patients. This result is in contrast with recent work demonstrating that 3-BrPa was well tolerated and beneficial in an animal model of arthritis (39), perhaps highlighting some uniqueness about the CNS. The parallel development of well-tolerated drugs that can specifically target immune cells metabolic demands could result in a wave of novel biologics to treat inflammatory disease.…”

Altered metabolic pathways regulate synovial inflammation in rheumatoid arthritis

“…These findings provide a rationale for the therapeutic targeting of specific lactate transporters on T cells in autoimmune diseases such as RA (reviewed in [38]). Furthermore, in animal models of arthritis 3-bromopyruvate (BrPA), a specific HK2 inhibitor, significantly decreased clinical arthritis scores in SKG mice, paralleled by an increase in the T reg /Th17 ratio [30]. Furthermore, in animal models of arthritis 3-bromopyruvate (BrPA), a specific HK2 inhibitor, significantly decreased clinical arthritis scores in SKG mice, paralleled by an increase in the T reg /Th17 ratio [30].…”

“…While the early increase in glycolysis is associated with elevated GLUT1 expression [61,62] and lactate production [59][60][61][62][63][64], the increased glucose demand by activated DCs is associated with the requirement of glucose-derived metabolic intermediates into the PPP and fatty acid synthesis to facilitate amino acid and protein synthesis for the secretion of proinflammatory mediators associated with DC activation. In the context of RA, while also modulating the T reg /Th17 ratio, BrPA-mediated blockade of HK2 suppressed DC activation and cytokine expression [30], suggesting that the glycolysis pathway may represent a potential therapeutic target in RA. Molecularly, TBK-IKKε/AKT signalling pathways and downstream target mammalian target of rapamycin (mTOR) have been strongly implicated in early activation of the glycolytic shift, which can be prevented by adhesion-related kinase (ARK) blockade [62].…”

“…REVIEW SERIES: TRANSLATING IMMUNOMETABOLISM [21,28,29], further perpetuating disease. In animal models of arthritis and in ex-vivo RA synovial tissue explants, several studies have shown that re-programming of these pathways with specific inhibitors leads to resolution of inflammation [21,[30][31][32][33][34].…”

Acacetin regulated the reciprocal differentiation of Th17 cells and Treg cells and mitigated the symptoms of collagen‐induced arthritis in mice

“…Epigallocatechin‐3‐gallate, an active constituent from green tea, was shown to rescue experimental autoimmune encephalomyelitis through the modulation of Th17 and Treg response in lymphoid tissues and central nervous system . In the field of RA, several components, such as tetrandrine, 3‐bromopyruvate and cryptotanshinone, showed their abilities to impact the balance of Th17/Treg response and, leading to alleviation of CIA symptoms in mice . Our results revealed a strong ability of acacetin to repress the development of CIA, reduce the production of auto‐reactive antibodies, and inhibit the proliferation of pathological T cells.…”