Dendritic cell-intrinsic LKB1-AMPK/SIK signaling controls metabolic homeostasis by limiting the hepatic Th17 response during obesity

Obesity-associated metabolic inflammation drives the development of insulin resistance and type 2 diabetes, notably through modulating innate and adaptive immune cells in metabolic organs. The nutrient sensor liver kinase B1 (LKB1) has recently been shown to control cellular metabolism and T cell priming functions of DCs. Here, we report that hepatic DCs from high-fat diet-fed (HFD-fed) obese mice display increased LKB1 phosphorylation and that LKB1 deficiency in DCs (CD11c Delta LKB1) worsened HFD-driven hepatic steatosis and impaired glucose homeostasis. Loss of LKB1 in DCs was associated with increased expression of Th17-polarizing cytokines and accumulation of hepatic IL-17A+ Th cells in HFD-fed mice. Importantly, IL-17A neutralization rescued metabolic perturbations in HFD-fed CD11c Delta LKB1 mice. Mechanistically, deficiency of the canonical LKB1 target AMPK in HFD-fed CD11c Delta AMPK alpha 1 mice recapitulated neither the hepatic Th17 phenotype nor the disrupted metabolic homeostasis, suggesting the involvement of other and/ or additional LKB1 downstream effectors. We indeed provide evidence that the control of Th17 responses by DCs via LKB1 is actually dependent on both AMPK alpha 1 salt-inducible kinase signaling. Altogether, our data reveal a key role for LKB1 signaling in DCs in protection against obesityinduced metabolic dysfunctions by limiting hepatic Th17 responses.Host-parasite interactio

Dendritic cells are what they eat: how their metabolism shapes T helper cell polarization

Dendritic cells (DCs) are professional antigen-presenting cells that play a crucial role in the priming and differentiation of CD4(+) T cells into several distinct subsets including effector T helper (Th) 1, Th17 and Th2 cells, as well as regulatory T cells (Tregs). It is becoming increasingly clear that cellular metabolism shapes the functional properties of DCs. Specifically, the ability of DCs to drive polarization of different Th cell subsets may be orchestrated by the engagement of distinct metabolic pathways. In this review, we will discuss the recent advances in the DC metabolism field, by focusing on how cellular metabolism of DCs shapes their priming and polarization of distinct Th cell responses.Host-parasite interactio

Increased stromal PFKFB3-mediated glycolysis in inflammatory bowel disease contributes to intestinal inflammation

Inflammatory bowel disease (IBD) is a chronic relapsing inflammation of the intestinal tract with currently not well-understood pathogenesis. In addition to the involvement of immune cells, increasing studies show an important role for fibroblasts in the pathogenesis of IBD. Previous work showed that glycolysis is the preferred energy source for fibroblasts in fibrotic diseases. 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase 3 (PFKFB3) is a key kinase supporting glycolysis. Increased expression of PFKFB3 in several cancers and inflammatory diseases has been previously reported, but the metabolic status of fibroblasts and the role of PFKFB3 in patients with IBD are currently unknown. Therefore, in this study, we evaluated the role of glycolysis and PFKFB3 expression in IBD. Single-sample gene set enrichment analysis (ssGSEA) revealed that glycolysis was significantly higher in IBD intestinal samples, compared to healthy controls, which was confirmed in the validation cohorts of IBD patients. Single-cell sequencing data indicated that PFKFB3 expression was higher in IBD-derived stromal cells. In vitro, PFKFB3 expression in IBD-derived fibroblasts was increased after the stimulation with pro-inflammatory cytokines. Using seahorse real-time cell metabolic analysis, inflamed fibroblasts were shown to have a higher extracellular acidification rate and a lower oxygen consumption rate, which could be reversed by inhibition of JAK/STAT pathway. Furthermore, increased expression of pro-inflammatory cytokines and chemokines in fibroblasts could be reverted by PFK15, a specific inhibitor of PFKFB3. In vivo experiments showed that PFK15 reduced the severity of dextran sulfate sodium (DSS)- and Tcell transfer induced colitis, which was accompanied by a reduction in immune cell infiltration in the intestines. These findings suggest that increased stromal PFKFB3 expression contributes to inflammation and the pathological function of fibroblasts in IBD. Inhibition of PFKFB3 suppressed their inflammatory characteristics

mTORC1 signaling in antigen-presenting cells of the skin restrains CD8(+) T cell priming

How mechanistic target of rapamycin complex 1 (mTORC1), a key regulator of cellular metabolism, affects dendritic cell (DC) metabolism and T cell-priming capacity has primarily been investigated in vitro, but how mTORC1 regulates this in vivo remains poorly defined. Here, using mice deficient for mTORC1 component raptor in DCs, we find that loss of mTORC1 negatively affects glycolytic and fatty acid metabolism and maturation of conventional DCs, particularly cDC1s. Nonetheless, antigen-specific CD8(+) T cell responses to infection are not compromised and are even enhanced following skin immunization. This is associated with increased activation of Langerhans cells and a subpopulation of EpCAM-expressing cDC1s, of which the latter show an increased physical interaction with CD8(+) T cells in situ. Together, this work reveals that mTORC1 limits CD8(+) T cell priming in vivo by differentially orchestrating the metabolism and immunogenicity of distinct antigen-presenting cell subsets, which may have implications for clinical use of mTOR inhibitors.Tumorimmunolog

Fasciola hepatica Fatty Acid Binding Protein 1 Modulates T cell Polarization by Promoting Dendritic Cell Thrombospondin-1 Secretion Without Affecting Metabolic Homeostasis in Obese Mice

BackgroundThe parasitic trematode Fasciola hepatica evades host immune defenses through secretion of various immunomodulatory molecules. Fatty Acid Binding Proteins (fhFABPs) are among the main excreted/secreted proteins and have been shown to display anti-inflammatory properties. However, little is currently known regarding their impact on dendritic cells (DCs) and their subsequent capacity to prime specific CD4(+) T cell subsets. Methodology/Principal FindingsThe immunomodulatory effects of both native F. hepatica extracts and recombinant fhFABPs were assessed on monocyte-derived human DCs (moDCs) and the underlying mechanism was next investigated using various approaches, including DC-allogenic T cell co-culture and DC phenotyping through transcriptomic, proteomic and FACS analyses. We mainly showed that fhFABP1 induced a tolerogenic-like phenotype in LPS-stimulated moDCs characterized by a dose-dependent increase in the cell-surface tolerogenic marker CD103 and IL-10 secretion, while DC co-stimulatory markers were not affected. A significant decrease in secretion of the pro-inflammatory cytokines IL-12p70 and IL-6 was also observed. In addition, these effects were associated with an increase in both Th2-on-Th1 ratio and IL-10 secretion by CD4(+) T cells following DC-T cell co-culture. RNA sequencing and targeted proteomic analyses identified thrombospondin-1 (TSP-1) as a non-canonical factor highly expressed and secreted by fhFABP1-primed moDCs. The effect of fhFABP1 on T cell skewing was abolished when using a TSP-1 blocking antibody during DC-T cell co-culture. Immunomodulation by helminth molecules has been linked to improved metabolic homeostasis during obesity. Although fhFABP1 injection in high-fat diet-fed obese mice induced a potent Th2 immune response in adipose tissue, it did not improved insulin sensitivity or glucose homeostasis. Conclusions/SignificanceWe show that fhFABP1 modulates T cell polarization, notably by promoting DC TSP-1 secretion in vitro, without affecting metabolic homeostasis in a mouse model of type 2 diabetes.Host-parasite interactio

LKB1 expressed in dendritic cells governs the development and expansion of thymus-derived regulatory T cells

Host-parasite interactio

Association Of Single Nucleotide Polymorphisms In The Gene Encoding Glut1 And Diabetic Nephropathy In Brazilian Patients With Type 1 Diabetes Mellitus

Mesangial cells subject to high extracellular glucose concentrations, as occur in hyperglycaemic states, are unable to down regulate glucose influx, resulting in intracellular activation of deleterious biochemical pathways. A high expression of GLUT1 participates in the development of diabetic glomerulopathy. Variants in the gene encoding GLUT1 (. SLC2A1) have been associated to this diabetic complication. The aim of this study was to test whether polymorphisms in SLC2A1 confer susceptibility to diabetic nephropathy (DN) in Brazilian type 1 diabetes patients. Four polymorphisms (rs3820589, rs1385129, rs841847 and rs841848) were genotyped in a Brazilian cohort comprised of 452 patients. A prospective analysis was performed in 155 patients. Mean duration of follow-up was 5.6. ±. 2.4. years and the incidence of renal events was 18.0%. The rs3820589 presented an inverse association with the prevalence of incipient DN (OR: 0.36, 95% CI: 0.16 - 0.80, p=. 0.01) and with progression to renal events (HR: 0.20; 95% CI: 0.03 - 0.70; p=. 0.009). AGGT and AGAC haplotypes were associated with the prevalence of incipient DN and the AGAC haplotype was also associated with the prevalence of established/advanced DN. In conclusion, rs3820589 in the SLC2A1 gene modulates the risk to DN in Brazilian patients with inadequate type 1 diabetes control.444170175Nishikawa, T., Edelstein, D., Brownlee, M., The missing link: a single unifying mechanism for diabetic complications (2000) Kidney Int Suppl, 77, pp. S26-S30Ayo, S.H., Radnik, R.A., Glass, W.F., Increased extracellular matrix synthesis and mRNA in mesangial cells grown in high-glucose medium (1991) Am J Physiol, 260, pp. F185-F191Sesso Rde, C., Lopes, A.A., Thome, F.S., Lugon, J.R., Watanabe, Y., Santos, D.R., Chronic dialysis in Brazil: report of the Brazilian dialysis census, 2011 (2012) J Bras Nefrol Orgao Oficial Soc Bras Lat Am Nefrol, 34, pp. 272-277Mauer, S.M., Steffes, M.W., Ellis, E.N., Sutherland, D.E., Brown, D.M., Goetz, F.C., Structural-functional relationships in diabetic nephropathy (1984) J Clin Invest, 74, pp. 1143-1155D'Agord Schaan, B., Lacchini, S., Bertoluci, M.C., Irigoyen, M.C., Machado, U.F., Schmid, H., Increased renal GLUT1 abundance and urinary TGF-beta 1 in streptozotocin-induced diabetic rats: implications for the development of nephropathy complicating diabetes (2001) Horm Metab Res Horm Stoffwechselforschung Horm Metab, 33, pp. 664-669Heilig, C.W., Liu, Y., England, R.L., D-glucose stimulates mesangial cell GLUT1 expression and basal and IGF-I-sensitive glucose uptake in rat mesangial cells: implications for diabetic nephropathy (1997) Diabetes, 46, pp. 1030-1039Henry, D.N., Busik, J.V., Brosius, F.C., Heilig, C.W., Glucose transporters control gene expression of aldose reductase, PKCalpha, and GLUT1 in mesangial cells in vitro (1999) Am J Physiol, 277, pp. F97-F104Weigert, C., Brodbeck, K., Brosius, F.C., Evidence for a novel TGF-beta1-independent mechanism of fibronectin production in mesangial cells overexpressing glucose transporters (2003) Diabetes, 52, pp. 527-535Seaquist, E.R., Goetz, F.C., Rich, S., Barbosa, J., Familial clustering of diabetic kidney disease. Evidence for genetic susceptibility to diabetic nephropathy (1989) N Engl J Med, 320, pp. 1161-1165Gross, J.L., de Azevedo, M.J., Silveiro, S.P., Canani, L.H., Caramori, M.L., Zelmanovitz, T., Diabetic nephropathy: diagnosis, prevention, and treatment (2005) Diabetes Care, 28, pp. 164-176Zintzaras, E., Stefanidis, I., Association between the GLUT1 gene polymorphism and the risk of diabetic nephropathy: a meta-analysis (2005) J Hum Genet, 50, pp. 84-91Cui, W., Du, B., Zhou, W., Relationship between five GLUT1 gene single nucleotide polymorphisms and diabetic nephropathy: a systematic review and meta-analysis (2012) Mol Biol Rep, 39, pp. 8551-8558Pimenta, J.R., Zuccherato, L.W., Debes, A.A., Color and genomic ancestry in Brazilians: a study with forensic microsatellites (2006) Hum Hered, 62, pp. 190-195Levey, A.S., Stevens, L.A., Schmid, C.H., A new equation to estimate glomerular filtration rate (2009) Ann Intern Med, 150, pp. 604-612Mohammedi, K., Maimaitiming, S., Emery, N., Allelic variations in superoxide dismutase-1 (SOD1) gene are associated with increased risk of diabetic nephropathy in type 1 diabetic subjects (2011) Mol Genet Metab, 104, pp. 654-660Kohner, E.M., The lesions and natural history of diabetic retinopathy (1991) Text Book of Diabetes, pp. 575-588. , editor, Oxford, Scientific BNyholt, D.R., A simple correction for multiple testing for single-nucleotide polymorphisms in linkage disequilibrium with each other (2004) Am J Hum Genet, 74, pp. 765-769Team, R.C., (2013) R: a language and environment for statistical computingTregouet, D.A., Garelle, V., A new JAVA interface implementation of THESIAS: testing haplotype effects in association studies (2007) Bioinformatics, 23, pp. 1038-1039Ng, D.P., Canani, L., Araki, S., Minor effect of GLUT1 polymorphisms on susceptibility to diabetic nephropathy in type 1 diabetes (2002) Diabetes, 51, pp. 2264-2269Murakami, T., Nishiyama, T., Shirotani, T., Identification of two enhancer elements in the gene encoding the type 1 glucose transporter from the mouse which are responsive to serum, growth factor, and oncogenes (1992) J Biol Chem, 267, pp. 9300-9306Heilig, C.W., Brosius, F.C., Cunningham, C., Role for GLUT1 in diabetic glomerulosclerosis (2006) Expert Rev Mol Med, 8, pp. 1-18Zeggini, E., Rayner, W., Morris, A.P., An evaluation of HapMap sample size and tagging SNP performance in large-scale empirical and simulated data sets (2005) Nat Genet, 37, pp. 1320-132

Catalase Activity, Allelic Variations In The Catalase Gene And Risk Of Kidney Complications In Patients With Type 1 Diabetes

Aims/hypothesis: Oxidative stress is involved in the pathogenesis of diabetic nephropathy. The antioxidant enzyme catalase plays a key role in redox regulation in the kidney. We investigated associations of catalase gene (CAT) polymorphisms and plasma catalase activity with diabetic nephropathy in type 1 diabetic patients. Methods: We genotyped nine single nucleotide polymorphisms (SNPs) in the CAT region in participants from the Survival Genetic Nephropathy (SURGENE) (340 French participants, 10 year follow-up) and the Génétique de la Néphropathie Diabétique (GENEDIAB) (444 Belgian and French participants, 8 year follow-up) study cohorts. Replication was performed in a Brazilian cross-sectional cohort (n = 451). Baseline plasma catalase activity was measured in SURGENE (n = 120) and GENEDIAB (n = 391) participants. Results: The A allele of rs7947841 was associated with the prevalence of incipient (OR 2.79, 95% CI 1.21, 6.24, p = 0.01) and established or advanced nephropathy (OR 5.72, 95% CI 1.62, 22.03, p = 0.007), and with the incidence of renal events, which were defined as new cases of microalbuminuria or progression to a more severe stage of nephropathy during follow-up (HR 1.82, 95% CI 1.13, 2.81, p = 0.01) in SURGENE participants. The same risk allele was associated with incipient nephropathy (OR 3.13, 95% CI 1.42, 7.24, p = 0.004) and with the incidence of end-stage renal disease (ESRD) (HR 2.11, 95% CI 1.23, 3.60, p = 0.008) in GENEDIAB participants. In both cohorts, the risk allele was associated with lower catalase activity. Associations with incipient and established or advanced nephropathy were confirmed in the replication cohort. Conclusions/interpretation: CAT variants were associated with the prevalence and incidence of diabetic nephropathy and ESRD in type 1 diabetic patients. 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