HGK/MAP4K4 deficiency induces TRAF2 stabilization and Th17 differentiation leading to insulin resistance.
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ABSTRACT:
SUBMITTER: Chuang HC
PROVIDER: S-EPMC4143962 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Type 2 diabetes (T2D) is a complex and heterogeneous disease. Obesity increases the risk of obese T2D; but in Asia non-obese T2D is prevalent. The cause of non-obese T2D has remained elusive. We studied the potential involvement of HGK/MAP4K4 in T2D using clinical samples from newly diagnosed, drug-naïve patients and healthy controls. HGK levels fell and IL-6 levels increased in T cells from T2D patients. Frequencies of IL-6-producing T cells were correlated with glucose levels after glucose-tolerance tests (but not body mass index and waist circumference) and inversely correlated with HGK expression levels. Moreover, methylation frequencies of the HGK promoter were increased in T2D patients and correlated with glucose levels after glucose-tolerance tests. The correlation was independent of body mass index. Demethylation treatment increased HGK expression levels and reduced IL-6 production in T2D T cells. This report identifies HGK methylation/downregulation in T cells as a potential biomarker for non-obese T2D.
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Project description:Protease-activated receptor 2 (PAR2) is a member of G-protein-coupled receptors and affects ligand-modulated calcium signaling. Although PAR2 signaling promotes obesity and adipose tissue inflammation in high fat- (HF-) fed conditions, its role in adipocyte differentiation under nonobesogenic conditions needs to be elucidated. Here, we used several tissues and primary-cultured adipocytes of mice lacking PAR2 to study its role in the development of adipose tissues. C57BL/6J mice with PAR2 deficiency exhibited a mild lipodystrophy-like phenotype in a chow diet-fed condition. When adipocyte differentiation was examined using primary-cultured preadipocytes, PAR2 deficiency led to a notable decrease in adipocyte differentiation and related protein expression, and PAR2 agonist treatment elevated adipocyte differentiation. Regarding the mechanism, PAR2-deficient preadipocytes exhibited impaired mitochondrial energy consumption. Further studies indicated that calcium-related signaling pathways for mitochondrial biogenesis are disrupted in the adipose tissues of PAR2-deficient mice and PAR2-deficient preadipocytes. Also, a PAR2 antagonist elevated mitochondrial reactive oxygen species and reduced the MitoTracker fluorescent signal in preadipocytes. Our studies revealed that PAR2 is important for the development of adipose tissue under basal conditions through the regulation of mitochondrial biogenesis and adipocyte differentiation.
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Project description:AIMS/HYPOTHESIS:Absent in melanoma 2 (AIM2) is a cytosolic sensor for double-stranded DNA and a tumour suppressor. Binding of double-stranded DNA to AIM2 forms the AIM2 inflammasome, leading to activation of caspase-1 and production of IL-1? and IL-18. Although inflammasome-independent effects of AIM2 have been reported, its role in energy metabolism is unknown. We aimed to evaluate the effect of AIM2 in energy metabolism and glucose homeostasis. METHODS:Male and female whole body Aim2 knockout (Aim2-/-) mice were used in the current study. Body weight, food intake, body composition, energy expenditure, fasting blood glucose levels, GTT and body temperature were measured at indicated time points. RNA sequencing was carried out on gonadal white adipose tissue (gWAT) in 14-month-old female mice. mRNA and protein levels in tissues were analysed by quantitative real-time PCR and immunoblot. Immune cell infiltration in gWAT was examined by flow cytometry. Stromal vascular fractions isolated from gWAT were used to investigate adipocyte differentiation. RESULTS:Male and female Aim2-/- mice were obese compared with wild-type controls from 7 weeks of age until 51 weeks of age, with increased adiposity in both subcutaneous and visceral fat depots. While there were no differences in food intake, Aim2-/- mice demonstrated decreased energy expenditure and impaired brown adipose tissue function compared with wild-type controls. Fasting glucose and insulin levels were elevated, and Aim2-/- mice were glucose intolerant on intraperitoneal GTT. RNA sequencing revealed marked upregulation of the IFN-inducible gene Ifi202b, which encodes protein 202 (p202) and elevated inflammatory signalling in gWAT of Aim2-/- mice. Increased infiltration of total and Ly6Clow monocytes was noted at 8 weeks of age in gWAT, before the onset of obesity and insulin resistance. Ifi202b knockdown blocked adipogenesis in stromal vascular fractions and reduced inflammation in bone marrow-derived macrophages, demonstrating a key role of p202 in mediating the increased adipogenesis and inflammation in Aim2-/- mice. CONCLUSIONS/INTERPRETATION:These results demonstrate a fundamental role for AIM2 in energy metabolism, inflammation and insulin resistance. Our studies establish a novel link between the innate immunity proteins, AIM2 and p202, and metabolism.
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Project description:Th17 cells produce IL-17, and the latter promotes bone loss in collagen-induced arthritis in mice. Blocking IL-17 action in mouse model of rheumatoid arthritis reduces disease symptoms. These observations suggest that Th17 cells may be involved in the pathogenesis of bone loss. However, the role of Th17 cell in estrogen (E2) deficiency-induced bone loss is still not very clear. We investigated the effect of E2 on Th17 differentiation in vivo and IL-17 mediated regulation of osteoclast and osteoblast differentiation. Additionally, effect of IL-17 functional block under E2 deficiency-induced bone loss was studied. In murine bone marrow cells, E2 suppressed IL-17 mediated osteoclast differentiation. IL-17 inhibited formation of mineralized nodules in osteoblasts and this effect was suppressed by E2. E2 treatment to mouse calvarial osteoblasts inhibited the IL-17-induced production of osteoclastogenic cytokines and NF-kB translocation. In ovariectomized mice, there was increase in the number of Th17 cells, transcription factors promoting Th17 cell differentiation and circulating IL-17 levels. These effects were reversed by E2 supplementation. Treatment of neutralizing IL-17 monoclonal antibody to Ovx mice mitigated the E2 deficiency-induced trabecular bone loss and reversed the decreased osteoprotegerin-to-receptor activator of nuclear factor kappa B ligand (RANKL) transcript levels in long bones, increased osteoclast differentiation from the bone marrow precursor cells and decreased osteoblast differentiation from the bone marrow stromal cells. Our findings indicate that E2 deficiency leads to increased differentiation of Th17 cells with attendant up regulation of STAT3, ROR-?t and ROR-? and downregulation of Foxp3 which antagonizes Th17 cell differentiation. Increased IL-17 production in turn induces bone loss by increasing pro-osteoclastogenic cytokines including TNF-?, IL-6 and RANKL from osteoblasts and functional block of IL-17 prevents bone loss. IL-17 thus plays a critical causal role in Ovx-induced bone loss and may be considered a potential therapeutic target in pathogenesis of post menopausal osteoporosis.
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Project description:TH17 differentiation is critically controlled by "signal 3" of cytokines (IL-6/IL-23) through STAT3. However, cytokines alone induced only a moderate level of STAT3 phosphorylation. Surprisingly, TCR stimulation alone induced STAT3 phosphorylation through Lck/Fyn, and synergistically with IL-6/IL-23 induced robust and optimal STAT3 phosphorylation at Y705. Inhibition of Lck/Fyn kinase activity by Srci1 or disrupting the interaction between Lck/Fyn and STAT3 by disease-causing STAT3 mutations selectively impaired TCR stimulation, but not cytokine-induced STAT3 phosphorylation, which consequently abolished TH17 differentiation and converted them to FOXP3+ Treg cells. Srci1 administration or disrupting the interaction between Lck/Fyn and STAT3 significantly ameliorated TH17 cell-mediated EAE disease. These findings uncover an unexpected deterministic role of TCR signaling in fate determination between TH17 and Treg cells through Lck/Fyn-dependent phosphorylation of STAT3, which can be exploited to develop therapeutics selectively against TH17-related autoimmune diseases. Our study thus provides insight into how TCR signaling could integrate with cytokine signal to direct T cell differentiation.
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Project description:It is known that differentiation of Th17 cells is promoted by activation of STAT3 and inhibited by activation of STAT1. Although both transcription factors are activated by several cytokines, including IL-6, IL-21, and IL-27, each of these cytokines has a very different effect on Th17 differentiation, ranging from strong induction (IL-6) to strong inhibition (IL-27). To determine the molecular basis for these differences, we measured STAT3 and STAT1 activation profiles for IL-6, IL-21, and IL-27, as well as for cytokine pairs over time. We found that the ratio of activated STAT3/activated STAT1 is crucial in determining whether cytokines promote or inhibit Th17 differentiation. IL-6 and IL-21 induced p-STAT3/p-STAT1 ratios > 1, leading to the promotion of Th17 differentiation, whereas IL-27 or IL-6+IL-27 induced p-STAT3/p-STAT1 ratios < 1, resulting in inhibition of Th17 differentiation. Consistent with these findings, we show that IL-27 induces sufficient p-STAT3 to promote Th17 differentiation in the absence of STAT1. Furthermore, IL-27-induced STAT1-deficient T cells were indistinguishable from bona fide highly proinflammatory Th17 cells because they induced severe experimental autoimmune encephalomyelitis upon adoptive transfer. Our results suggest that the ratio of p-STAT3/p-STAT1 induced by a cytokine or cytokine pairs can be used to predict whether they induce a competent Th17-differentiation program.
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Project description:Rheumatoid arthritis (RA) is an inflammatory disease in which interleukin 17 (IL-17)-producing T helper 17 (T(H)17) cells have been critically involved. We show that in patients with RA, the expression of a multifunctional regulator ?-arrestin1 was significantly up-regulated in peripheral and synovial CD4(+) T cells, which correlated well with active phases of RA. In collagen-induced arthritis, deficiency of ?-arrestin1 ameliorated disease with decreased T(H)17 cell differentiation, proinflammatory cytokine production, synovitis, and cartilage and bone destruction. Further mechanistic study reveals that ?-arrestin1 promoted signal transducer and activator of transcription 3 (STAT3) activation required for T(H)17 cell differentiation through scaffolding the interaction of Janus kinase 1 and STAT3. These findings indicate a critical role for ?-arrestin1 in the pathogenesis of collagen-induced arthritis and T(H)17 cell differentiation and suggest ?-arrestin1 as a potential diagnostic biomarker and therapeutic target for RA.
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Project description:Obesity is a causal factor of type 2 diabetes (T2D); however, people without obesity (including lean, normal weight, or overweight) may still develop T2D. Non-obese T2D is prevalent in Asia and also frequently occurs in Europe. Recently, multiple evidences oppose the notion that either obesity or central obesity (visceral fat accumulation) promotes non-obese T2D. Several factors such as inflammation and environmental factors contribute to non-obese T2D. According to the data derived from gene knockout mice and T2D clinical samples in Asia and Europe, the pathogenesis of non-obese T2D has been unveiled recently. MAP4K4 downregulation in T cells results in enhancement of the IL-6+ Th17 cell population, leading to insulin resistance and T2D in both human and mice. Moreover, MAP4K4 single nucleotide polymorphisms and epigenetic changes are associated with T2D patients. Interactions between MAP4K4 gene variants and environmental factors may contribute to MAP4K4 attenuation in T cells, leading to non-obese T2D. Future investigations of the pathogenesis of non-obese T2D shall lead to development of precision medicine for non-obese T2D.
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