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Project description:Foxp3low inflammatory non-suppressive (INS)-regulatory T cells (Tregs) were discovered recently. Unlike conventional Tregs, they produce proinflammatory-cytokines, exhibit reduced suppressiveness, and promote rather than impair anti-tumor immunity. The role of mitochondria in Foxp3low INS-Treg formation in vivo is unclear. We showed that the Foxp3low INS-Treg equivalents in human tumors demonstrate attenuated expression of CRIF1, a vital mitochondrial regulator. Mice with CRIF1 deficiency in Tregs bore Foxp3low INS-Tregs with mitochondrial dysfunction. The -ketoglutarate-mTORC1 axis was enhanced in these cells. This promoted proinflammatory-cytokine expression by inducing EOMES and SATB1 expression. Moreover, chromatin openness of the regulatory regions of the Ifng and Il4 genes was increased, which facilitated EOMES/SATB1 binding. The increased -ketoglutarate-derived 2-hydroxyglutarate downregulated Foxp3 expression by methylating the Foxp3-gene regulatory regions. Furthermore, CRIF1-deficiency-induced Foxp3low INS-Tregs suppressed tumor growth in an IFN- dependent manner. Thus, CRIF1-mediated mitochondrial homeostasis is critical for inducing Foxp3low INS-Tregs that promote anti-tumor immunity.
2024-02-28 | GSE233902 | GEO
Project description:Foxp3low inflammatory non-suppressive (INS)-regulatory T cells (Tregs) were discovered recently. Unlike conventional Tregs, they produce proinflammatory-cytokines, exhibit reduced suppressiveness, and promote rather than impair anti-tumor immunity. The role of mitochondria in Foxp3low INS-Treg formation in vivo is unclear. We showed that the Foxp3low INS-Treg equivalents in human tumors demonstrate attenuated expression of CRIF1, a vital mitochondrial regulator. Mice with CRIF1 deficiency in Tregs bore Foxp3low INS-Tregs with mitochondrial dysfunction. The -ketoglutarate-mTORC1 axis was enhanced in these cells. This promoted proinflammatory-cytokine expression by inducing EOMES and SATB1 expression. Moreover, chromatin openness of the regulatory regions of the Ifng and Il4 genes was increased, which facilitated EOMES/SATB1 binding. The increased -ketoglutarate-derived 2-hydroxyglutarate downregulated Foxp3 expression by methylating the Foxp3-gene regulatory regions. Furthermore, CRIF1-deficiency-induced Foxp3low INS-Tregs suppressed tumor growth in an IFN- dependent manner. Thus, CRIF1-mediated mitochondrial homeostasis is critical for inducing Foxp3low INS-Tregs that promote anti-tumor immunity.
2024-02-28 | GSE233901 | GEO
Project description:Mitochondrial dysfunction has been implicated in the pathophysiology of various cardiovascular diseases. CRIF1 is a protein present in the mitochondria associated with large mitoribosomal subunits, and CRIF1 knockdown induces mitochondrial dysfunction and promotes ROS production. p66shc is a redox enzyme implicated in mitochondrial ROS generation and translation of oxidative signals and, therefore, is a key factor for oxidative stress in endothelial cells. In this study, we investigated whether mitochondrial dysfunction induced by CRIF1 knockdown induces p66shc stimulation and plays any role in mitochondrial dysfunction-induced endothelial activation. Knockdown of CRIF1 decreased the expression of mitochondrial oxidative phosphorylation (OXPHOS) complexes I, III and IV, leading to increased mitochondrial ROS (mtROS) and hyperpolarization of the mitochondrial membrane potential. Knockdown of CRIF1 also stimulated phosphorylation of p66shc and increased cytosolic ROS in endothelial cells. Furthermore, the expression of vascular cell adhesion molecule-1 and endoplasmic reticulum stress proteins were increased upon CRIF1 knockdown in endothelial cells. However, p66shc knockdown blunted the alteration in mitochondrial dynamics and ROS production in CRIF1 knockdown endothelial cells. In addition, p66shc knockdown reduced the CRIF1 knockdown-induced increases in adhesion between monocytes and endothelial cells. Taken together, these results suggest that CRIF1 knockdown partially induces endothelial activation via increased ROS production and phosphorylation of p66shc.
| S-EPMC4048193 | biostudies-literature
Project description:BackgroundLike other helminths, hookworms (HW) induce a regulatory immune response able to modulate and dampen reactivity of the host to antigens. No data about the evolution of the immune response after treatment are available. We aim to phenotype the regulatory immune response during natural HW infection and its evolution after treatment.MethodologyTwenty hookworm infected (HW+) and 14 non-infected subjects HW-from endemic area in the periphery of Ho Chi Minh City were included. Blood and feces samples were obtained before, 2 and 4 weeks after treatment with Albendazole 400mg. Additional samples were obtained at 3 and 12 months in the HW+ group. Hematological parameters, Treg (CD4+CD25hiFoxP3hi) and surface molecules (CD39, CD62L, ICOS, PD-1, CD45RA) were measured as well as inflammatory and lymphocytes differentiation cytokines such as IL-1β, IL-6, IFNγ, IL-4, IL-17, IL-10, IL-2 and TGFβ.ResultsHW+ subjects showed higher Treg, TregICOS+, Treg PD1-, TregCD62L+ and CD45RA+FoxP3lo resting Treg (rTreg). CD45RA-FoxP3lo non-suppressive Treg cells were also increased. No preferential Th1/Th2 orientation was observed, nor difference for IL-10 between two groups. After treatment, Treg, TregICOS+, TregCD62L+, Treg PD1- and rTreg decreased while IL-4 and IL-6 cytokines increased.ConclusionDuring HW infection, Treg are increased and characterized by a heterogeneous population: a highly suppressive as well as a non-suppressive T cells phenotype. After treatment, Treg with immune-suppressive phenotype exhibited a decrease parallel to an inflammatory Th2 response.
| S-EPMC8191899 | biostudies-literature
Project description:Recent studies have implicated mitochondrial disruption in podocyte dysfunction, which is a characteristic feature of primary and diabetic glomerular diseases. However, the mechanisms by which primary mitochondrial dysfunction in podocytes affects glomerular renal diseases are currently unknown. To investigate the role of mitochondrial oxidative phosphorylation (OxPhos) in podocyte dysfunction, glomerular function was examined in mice carrying a loss of function mutation of the gene encoding CR6-interacting factor-1 (CRIF1), which is essential for intramitochondrial production and the subsequent insertion of OxPhos polypeptides into the inner mitochondrial membrane. Homozygotic deficiency of CRIF1 in podocytes resulted in profound and progressive albuminuria from 3 weeks of age; the CRIF1-deficient mice also developed glomerular and tubulointerstitial lesions by 10 weeks of age. Furthermore, marked glomerular sclerosis and interstitial fibrosis were observed in homozygous CRIF1-deficient mice at 20 weeks of age. In cultured mouse podocytes, loss of CRIF1 resulted in OxPhos dysfunction and marked loss or abnormal aggregation of F-actin. These findings indicate that the OxPhos status determines the integrity of podocytes and their ability to maintain a tight barrier and control albuminuria. Analyses of the glomerular function of the podocyte-specific primary OxPhos dysfunction model mice demonstrate a link between podocyte mitochondrial dysfunction, progressive glomerular sclerosis, and tubulointerstitial diseases.
| S-EPMC8124436 | biostudies-literature
Project description:Rho GDP-dissociation inhibitor (RhoGDI), a downregulator of Rho family GTPases, prevents nucleotide exchange and membrane association. It is responsible for the activation of Rho GTPases, which regulate a variety of cellular processes, such as migration. Although RhoGDI2 has been identified as a tumor suppressor gene involved in cellular migration and invasion, little is known about its role in vascular endothelial cell (EC) migration. CR6-interacting factor 1 (CRIF1) is a CR6/GADD45-interacting protein with important mitochondrial functions and regulation of cell growth. We examined the expression of RhoGDI2 in CRIF1-deficient human umbilical vein endothelial cells (HUVECs) and its role in cell migration. Expression of RhoGDI2 was found to be considerably higher in CRIF1-deficient HUVECs along with suppression of cell migration. Moreover, the phosphorylation levels of Akt and CREB were decreased in CRIF1-silenced cells. The Akt-CREB signaling pathway was implicated in the changes in endothelial cell migration caused by CRIF1 downregulation. In addition to RhoGDI2, we identified another factor that promotes migration and invasion of ECs. Adrenomedullin2 (ADM2) is an autocrine/paracrine factor that regulates vascular tone and other vascular functions. Endogenous ADM2 levels were elevated in CRIF1-silenced HUVECs with no effect on cell migration. However, siRNA-mediated depletion of RhoGDI2 or exogenous ADM2 administration significantly restored cell migration via the Akt-CREB signaling pathway. In conclusion, RhoGDI2 and ADM2 play important roles in the migration of CRIF1-deficient endothelial cells.
| S-EPMC8389428 | biostudies-literature
Project description:Previous work using non-invasive radiofrequency field treatment (RFT) in cancer has demonstrated its therapeutic potential as it can increase intratumoral blood perfusion, localization of intravenously delivered drugs, and promote a hyperthermic intratumoral state. Despite the well-known immunologic benefits that febrile hyperthermia can induce, an investigation of how RFT could modulate the intra-tumoral immune microenvironment had not been studied. Thus, using an established 4T1 breast cancer model in immune competent mice, we demonstrate that RFT induces a transient, localized, and T-cell dependent intratumoral inflammatory response. More specifically we show that multi- and singlet-dose RFT promote an increase in tumor volume in immune competent Balb/c mice, which does not occur in athymic nude models. Further leukocyte subset analysis at 24, 48, and 120?hours after a single RFT show a rapid increase in tumoral trafficking of CD4+ and CD8+ T-cells 24?hours post-treatment. Additional serum cytokine analysis reveals an increase in numerous pro-inflammatory cytokines and chemokines associated with enhanced T-cell trafficking. Overall, these data demonstrate that non-invasive RFT could be an effective immunomodulatory strategy in solid tumors, especially for enhancing the tumoral trafficking of lymphocytes, which is currently a major hindrance of numerous cancer immunotherapeutic strategies.
| S-EPMC5823899 | biostudies-other
Project description:Regulatory T cells (Treg cells), a distinct subset of CD4+ T cells, are necessary for the maintenance of immune self-tolerance and homeostasis1,2. Recent studies have demonstrated that Treg cells exhibit a unique metabolic profile, characterized by an increase in mitochondrial metabolism relative to other CD4+ effector subsets3,4. Furthermore, the Treg cell lineage-defining transcription factor, Foxp3, has been shown to promote respiration5,6; however, it remains unknown whether the mitochondrial respiratory chain is required for the T cell-suppression capacity, stability and survival of Treg cells. Here we report that Treg cell-specific ablation of mitochondrial respiratory chain complex III in mice results in the development of fatal inflammatory disease early in life, without affecting Treg cell number. Mice that lack mitochondrial complex III specifically in Treg cells displayed a loss of T cell-suppression capacity without altering Treg cell proliferation and survival. Treg cells deficient in complex III showed decreased expression of genes associated with Treg function, whereas Foxp3 expression remained stable. Loss of complex III in Treg cells increased DNA methylation as well as the metabolites 2-hydroxyglutarate (2-HG) and succinate that inhibit the ten-eleven translocation (TET) family of DNA demethylases7. Thus, Treg cells require mitochondrial complex III to maintain immune regulatory gene expression and suppressive function.
| S-EPMC6345596 | biostudies-literature
Project description:Cerebral endothelial cells (ECs) require junctional proteins to maintain blood-brain barrier (BBB) integrity, restricting toxic substances and controlling peripheral immune cells with a higher concentration of mitochondria than ECs of peripheral capillaries. The mechanism underlying BBB disruption by defective mitochondrial oxidative phosphorylation (OxPhos) is unclear in a mitochondria-related gene-targeted animal model. To assess the role of EC mitochondrial OxPhos function in the maintenance of the BBB, we developed an EC-specific CR6-interactin factor1 (Crif1) deletion mouse. We clearly observed defects in motor behavior, uncompacted myelin and leukocyte infiltration caused by BBB maturation and disruption in this mice. Furthermore, we investigated the alteration in the actin cytoskeleton, which interacts with junctional proteins to support BBB integrity. Loss of Crif1 led to reorganization of the actin cytoskeleton and a decrease in tight junction-associated protein expression through an ATP production defect in vitro and in vivo. Based on these results, we suggest that mitochondrial OxPhos is important for the maturation and maintenance of BBB integrity by supplying ATP to cerebral ECs.
| S-EPMC7308523 | biostudies-literature
Project description:Paradoxical observations have been made regarding the role of caveolin-1 (Cav-1) during cellular senescence. For example, caveolin-1 deficiency prevents reactive oxygen species-induced cellular senescence despite mitochondrial dysfunction, which leads to senescence. To resolve this paradox, we re-addressed the role of caveolin-1 in cellular senescence in human diploid fibroblasts, A549, HCT116, and Cav-1-/- mouse embryonic fibroblasts. Cav-1 deficiency (knockout or knockdown) induced cellular senescence via a p53-p21-dependent pathway, downregulating the expression level of the cardiolipin biosynthesis enzymes and then reducing the content of cardiolipin, a critical lipid for mitochondrial respiration. Our results showed that Cav-1 deficiency decreased mitochondrial respiration, reduced the activity of oxidative phosphorylation complex I (CI), inactivated SIRT1, and decreased the NAD+ /NADH ratio. From these results, we concluded that Cav-1 deficiency induces premature senescence via mitochondrial dysfunction and silent information regulator 2 homologue 1 (SIRT1) inactivation.
| S-EPMC5506423 | biostudies-literature