Geranylgeranyl pyrophosphate amplifies T_reg differentiation via increased IL‐2 expression to ameliorate DSS‐induced colitis

Abstract

Blocking the mevalonate pathway for cholesterol reduction by using statin may have adverse effects including statin‐induced colitis. Moreover, one of the predisposing factors for colitis is an imbalanced CD4+ T cell, which can be observed on the complete deletion of HMG‐CoA reductase (HMGCR), a target of statins. In this study, we inquired geranylgeranyl pyrophosphate (GGPP) is responsible for maintaining the T‐cell homeostasis. Following dextran sulfate sodium (DSS)‐induced colitis, simvastatin increased the severity of disease, while cotreatment with GGPP, but not with cholesterol, reversed the disease magnitude. GGPP ameliorated DSS‐induced colitis by increasing Treg cells. GGPP amplified Treg differentiation through increased IL‐2/STAT 5 signaling. GGPP prenylated Ras protein, a prerequisite for extracellular signal‐regulated kinase (ERK) pathway activation, leading to increased IL‐2 production. Higher simvastatin dose increased the severity of colitis. GGPP ameliorated simvastatin‐increased colitis by increasing Treg cells. Treg cells, which have the capacity to suppress inflammatory T cells and were generated through IL‐2/STAT5 signaling, increased IL‐2 production through prenylation and activation of the Ras/ERK pathway.

Cholesterol metabolism: a new molecular switch to control inflammation

“…As a consequence, host cells down-regulate their lipid metabolism upon microbial sensing to protect the body from infection. Pathogens are sensed by TLR, that together with engagement of type I IFN receptors, have a general outcome to downregulate cholesterol metabolism in order to deplete energy reserves that might be used by the pathogen for propagation [41][42][43][44][45]. Coupled to this response is the regulation of the inflammatory cascade and the macrophage's effector function, demonstrating the intricate relationship between cholesterol metabolism and the immune response in innate immune cells.…”

“…The provision of GGPP is also important, regulating autophagy, cell size and division in the Jurkat T cell line [114]. More recently, it has been shown that GGPP is a key metabolite in the maintenance of the Treg pool in a mouse model of colitis, amplifying Treg differentiation through STAT5 phosphorylation and decreasing pathogenic Th1 and Th17 responses [45]. The CBP also provides 7-dihydrocholesterol, the precursor of immunomodulatory vitamin D3, which has been directly implicated in the regulation of immune responses via its ability to induce the production of IL-10, a potent anti-inflammatory cytokine [115] and key to the immune-resolution process [116].…”

Mechanisms of exTreg induction

“…Impairment of OXPHOS by deletion of its regulator proteins peroxisome proliferator-activated receptor γ coactivator 1α (Pgc1α) or sirtuin 3 (Sirt3), inhibits Treg functional fitness in vitro and in a mouse model of allograft survival [77]. Pandit et al [78] showed IL-2/STAT5 signaling is mediated through geranylgeranyl pyrophosphate. In a dextran sulfate sodium-induced colitis mouse model, they demonstrated that geranylgeranyl pyrophosphate-induced Ras/ERK enhanced IL-2 production in CD4 + T cells and lead to IL-2/STAT5 signaling to increase Treg differentiation and stability.…”

“…Pandit et al. [78] showed IL‐2/STAT5 signaling is mediated through geranylgeranyl pyrophosphate. In a dextran sulfate sodium‐induced colitis mouse model, they demonstrated that geranylgeranyl pyrophosphate‐induced Ras/ERK enhanced IL‐2 production in CD4 + T cells and lead to IL‐2/STAT5 signaling to increase Treg differentiation and stability.…”

Comparative Transcriptomic Analysis Reveals the Immunosuppressive Targets of Mesalazine in Dextran Sulfate Sodium-Induced Ulcerative Colitis

“…For example, a study using a T cell transfer colitis model demonstrated that CD4(+) T helper cells strongly contributed to the pathogenesis of IBD (Maschmeyer et al, 2021). In addition, imbalanced CD4+ T cells have been reported as predisposing factors for colitis (Pandit et al, 2021). Furthermore, mesalazine treatment mediated cytokine biosynthesis and secretion.…”