Sustained IFN-I stimulation impairs MAIT cell responses to bacteria by inducing IL-10 during chronic HIV-1 infection.
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ABSTRACT:
SUBMITTER: Tang X
PROVIDER: S-EPMC7030930 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:CD4+ T cells that produce IFN-? are the source of host-protective IL-10 during primary infection with a number of different pathogens, including Plasmodium spp. The fate of these CD4+IFN-?+IL-10+ T cells following clearance of primary infection and their subsequent influence on the course of repeated infections is, however, presently unknown. In this study, utilizing IFN-?-yellow fluorescent protein (YFP) and IL-10-GFP dual reporter mice, we show that primary malaria infection-induced CD4+YFP+GFP+ T cells have limited memory potential, do not stably express IL-10, and are disproportionately lost from the Ag-experienced CD4+ T cell memory population during the maintenance phase postinfection. CD4+YFP+GFP+ T cells generally exhibited a short-lived effector rather than effector memory T cell phenotype postinfection and expressed high levels of PD-1, Lag-3, and TIGIT, indicative of cellular exhaustion. Consistently, the surviving CD4+YFP+GFP+ T cell-derived cells were unresponsive and failed to proliferate during the early phase of secondary infection. In contrast, CD4+YFP+GFP- T cell-derived cells expanded rapidly and upregulated IL-10 expression during secondary infection. Correspondingly, CD4+ T cells were the major producers within an accelerated and amplified IL-10 response during the early stage of secondary malaria infection. Notably, IL-10 exerted quantitatively stronger regulatory effects on innate and CD4+ T cell responses during primary and secondary infections, respectively. The results in this study significantly improve our understanding of the durability of IL-10-producing CD4+ T cells postinfection and provide information on how IL-10 may contribute to optimized parasite control and prevention of immune-mediated pathology during repeated malaria infections.
| S-EPMC5055201 | biostudies-other
Project description:Venous thromboembolism (VTE) is a leading cause of preventable deaths in hospitals, and its incidence is not decreasing despite extensive efforts in clinical and laboratory research. Venous thrombi are primarily formed in the valve pockets of deep veins, where activated monocytes play a crucial role in bridging innate immune activation and hemostatic pathways through the production of inflammatory cytokines, chemokines, and tissue factor (TF) - a principal initiator of coagulation. In the valve pocket inflammation and hypoxia (sustained/intermittent) coexist, however their combined effects on immunothrombotic processes are poorly understood. Inflammation is strongly associated with VTE, while the additional contribution of hypoxia remains largely unexplored. To investigate this, we modelled the intricate conditions of the venous valve pocket using a state-of-the-art hypoxia chamber with software-controlled oxygen cycling. We comprehensively studied the effects of sustained and intermittent hypoxia alone, and in combination with VTE-associated inflammatory stimuli on primary monocytes. TF expression and activity was measured in monocytes subjected to sustained and intermittent hypoxia alone, or in combination with IL-1β. Monocyte responses were further analyzed in detailed by RNA sequencing and validated by ELISA. Stimulation with IL-1β alone promoted both transcription and activity of TF. Interestingly, the stimulatory effect of IL-1β on TF was attenuated by sustained hypoxia, but not by intermittent hypoxia. Our transcriptome analysis further confirmed that sustained hypoxia limited the pro-inflammatory response induced by IL-1β, and triggered a metabolic shift in monocytes. Intermittent hypoxia alone had a modest effect on monocyte transcript. However, in combination with IL-1β intermittent hypoxia significantly altered the expression of 2207 genes and enhanced the IL-1β-stimulatory effects on several chemokine and interleukin genes (e.g., IL-19, IL-24, IL-32, MIF), as well as genes involved in coagulation (thrombomodulin) and fibrinolysis (VEGFA, MMP9, MMP14 and PAI-1). Increased production of CCL2, IL-6 and TNF following stimulation with intermittent hypoxia and IL-1β was confirmed by ELISA. Our findings provide valuable insights into how the different hypoxic profiles shape the immunothrombotic response of monocytes and shed new light on the early events in the pathogenesis of venous thrombosis.
| S-EPMC10518394 | biostudies-literature
Project description:BACKGROUND:While Syk has been shown to associate with TLR4, the immune consequences of Syk-TLR interactions and related molecular mechanisms are unclear. METHODS:Gain- and loss-of-function approaches were utilized to determine the regulatory function of Syk and elucidate the related molecular mechanisms in TLR4-mediated inflammatory responses. Cytokine production was measured by ELISA and phosphorylation of signaling molecules determined by Western blotting. RESULTS:Syk deficiency in murine dendritic cells resulted in the enhancement of LPS-induced IFN? and IL-10 but suppression of pro-inflammatory cytokines (TNF?, IL-6). Deficiency of Syk enhanced the activity of PI3K and elevated the phosphorylation of PI3K and Akt, which in turn, lead to the phospho-inactivation of the downstream, central gatekeeper of the innate response, GSK3?. Inhibition of PI3K or Akt abrogated the ability of Syk deficiency to enhance IFN? and IL-10 in Syk deficient cells, confirmed by the overexpression of Akt (Myr-Akt) or constitutively active GSK3? (GSK3 S9A). Moreover, neither inhibition of PI3K-Akt signaling nor neutralization of de novo synthesized IFN? could rescue TNF? and IL-6 production in LPS-stimulated Syk deficient cells. Syk deficiency resulted in decreased phosphorylation of IKK? and the NF-?B p65 subunit, further suggesting a divergent influence of Syk on pro- and anti-inflammatory TLR responses. CONCLUSIONS:Syk negatively regulates TLR4-mediated production of IFN? and IL-10 and promotes inflammatory responses in dendritic cells through divergent regulation of downstream PI3K-Akt and NF-?B signaling pathways. GENERAL SIGNIFICANCE:Syk may represent a novel target for manipulating the direction or intensity of the innate response, depending on clinical necessity.
| S-EPMC5321715 | biostudies-literature
Project description:Immunity to malaria is widely believed to wane in the absence of reinfection, but direct evidence for the presence or absence of durable immunological memory to malaria is limited. Here, we analysed malaria-specific CD4+ T cell responses of individuals living in an area of low malaria transmission in northern Thailand, who had had a documented clinical attack of P. falciparum and/or P. vivax in the past 6 years. CD4+ T cell effector memory (CD45RO+) IFN-? (24 hours ex vivo restimulation) and cultured IL-10 (6 day secretion into culture supernatant) responses to malaria schizont antigens were detected only in malaria-exposed subjects and were more prominent in subjects with long-lived antibodies or memory B cells specific to malaria antigens. The number of IFN-?-producing effector memory T cells declined significantly over the 12 months of the study, and with time since last documented malaria infection, with an estimated half life of the response of 3.3 (95% CI 1.9-10.3) years. In sharp contrast, IL-10 responses were sustained for many years after last known malaria infection with no significant decline over at least 6 years. The observations have clear implications for understanding the immunoepidemiology of naturally acquired malaria infections and for malaria vaccine development.
| S-EPMC3037361 | biostudies-literature
Project description:We replicated the intricate conditions of the venous valve pocket using a state-of-the-art hypoxia chamber with software-controlled oxygen cycling. We comprehensively studied the effects of sustained and intermitted hypoxia alone or in combination with IL-1b to mimic VTE-associated inflammatory stimuli on primary monocytes. Our transcriptome analysis revealed that sustained hypoxia limited the pro-inflammatory response induced by IL-1b, and triggered a metabolic shift in the monocyte transcriptome. On the other hand, intermittent hypoxia alone had a modest effect, but in combination with IL-1b it significant altered the expression of 2207 genes. Notably, intermittent hypoxia enhanced the IL-1b -stimulatory effects on several chemokine and interleukin genes (e.g., IL-19, IL-24, IL-32, MIF), as well as genes involved in coagulation (thrombomodulin) and fibrinolysis (VEGFA, MMP9, MMP14 and PAI-1. The RNA seq data are paired with validations on protein level in the published paper. Our findings provide valuable insights into how the different hypoxic profiles shape the immunothrombotic response of monocytes and shed new light on the early events in the pathogenesis of venous thrombosis.
2023-06-15 | GSE234701 | GEO
Project description:BackgroundProduction of interferon (IFN)-gamma is key to efficient anti-tumor immunity. The present study was set out to investigate effects of IFNgamma on the release of the potent pro-angiogenic mediator IL-8 by human A549 lung carcinoma cells.MethodsA549 cells were cultured and stimulated with interleukin (IL)-1beta alone or in combination with IFNgamma. IL-8 production by these cells was analyzed with enzyme linked immuno sorbent assay (ELISA). mRNA-expression was analyzed by real-time PCR and RNase protection assay (RPA), respectively. Expression of inhibitor-kappa Balpha, cellular IL-8, and cyclooxygenase-2 was analyzed by Western blot analysis.ResultsHere we demonstrate that IFNgamma efficiently reduced IL-8 secretion under the influence of IL-1beta. Surprisingly, real-time PCR analysis and RPA revealed that the inhibitory effect of IFNgamma on IL-8 was not associated with significant changes in mRNA levels. These observations concurred with lack of a modulatory activity of IFNgamma on IL-1beta-induced NF-kappaB activation as assessed by cellular IkappaB levels. Moreover, analysis of intracellular IL-8 suggests that IFNgamma modulated IL-8 secretion by action on the posttranslational level. In contrast to IL-8, IL-1beta-induced cyclooxygenase-2 expression and release of IL-6 were not affected by IFNgamma indicating that modulation of IL-1beta action by this cytokine displays specificity.ConclusionData presented herein agree with an angiostatic role of IFNgamma as seen in rodent models of solid tumors and suggest that increasing T helper type 1 (Th1)-like functions in lung cancer patients e.g. by local delivery of IFNgamma may mediate therapeutic benefit via mechanisms that potentially include modulation of pro-angiogenic IL-8.
| S-EPMC2556346 | biostudies-literature
Project description:Innate immune responses must be regulated in the intestine to prevent excessive inflammation. Here, using gene reporter mice, we show that a subset of mouse colonic macrophages constitutively produced the anti-inflammatory cytokine IL-10. In mice infected with Citrobacter rodentium, which is considered similar to enteropathogenic Escherichia coli infection in humans, macrophage IL-10 was required to prevent intestinal pathology and to promote survival. The synthesis of the proinflammatory cytokine IL-23 was significantly increased in infected mice with a myeloid cell specific deletion of IL-10 and the addition of IL-10 reduced in vitro IL-23 production by intestinal macrophages. Furthermore, blockade of IL-23 led to reduced morbidity and mortality in the context of macrophage IL-10 deficiency. Transcriptome analysis indicated that the reporter positive and negative colonic macrophage subsets were highly similar, but the reporter positive cells differed for the expression of CD163, an IL-10 target gene, suggesting an autocrine IL-10 signal, and when obtained from infected mice, they had reduced IL-23p19 mRNA. Interestingly, only transfer of the reporter positive cells could rescue IL-10 deficient infected mice. Therefore, these data indicate a pivotal role for a subset of intestinal macrophages that constitutively produces IL-10, perhaps acting in part in autocrine fashion, in controlling excessive innate immune activation, regulation of IL-23 production, and prevention of tissue damage after an acute bacterial infection in the intestine.
2015-05-12 | GSE58677 | GEO
Project description:Joint trauma leads to post-traumatic inflammation with upregulation of inflammatory cytokines and degradative enzymes. If severe enough, this response can lead to irreversible post-traumatic osteoarthritis. Interleukin-10 (IL-10), a cytokine with potent anti-inflammatory effects, has been shown to have chondroprotective effects. A gene therapy approach using a vector to overexpress IL-10 in the joint represents a feasible method of delivering sustained high doses of IL-10 to post-traumatic joints. We hypothesized that an AAV5 vector overexpressing IL-10 would result in rapid and sustained IL-10 expression following direct intra-articular injection and that this increase would not be reflected in systemic circulation. In addition, we hypothesized that intra-articular AAV5-IL-10 injection would not induce a local inflammatory response. Twelve horses were assigned to either treatment (AAV5-IL-10-injected) or control (PBS-injected) groups. Middle carpal joints were injected with 1012 vector genomes/joint or phosphate-buffered saline (PBS) alone (3 mL). Serial synovial fluid samples were analyzed for inflammatory changes, IL-10 concentration, and vector genome copy number. Serum samples were also analyzed for IL-10 concentration and vector genome copy number. Synovial membrane was collected on day 84. Synovial fluid IL-10 was significantly increased within 48 h of AAV5-IL-10 injection and remained increased, compared to PBS-injected joints, until day 84. Serum IL-10 was not different between groups. Vector administration did not cause a significant synovial inflammatory response. Vector genomes were detectable in the plasma, synovial fluid, and synovial membrane of AAV5-IL-10-injected horses only. IL-10 has the potential to modulate the articular inflammatory response, thereby protecting cartilage from degradation and osteoarthritis. This study demonstrates the feasibility and efficiency of intra-articular AAV5-IL-10, and future studies investigating the chondroprotective effects of IL-10 in inflamed joints in vivo are warranted.
| S-EPMC7872004 | biostudies-literature
Project description:Innate immune responses must be regulated in the intestine to prevent excessive inflammation. Here, using gene reporter mice, we show that a subset of mouse colonic macrophages constitutively produced the anti-inflammatory cytokine IL-10. In mice infected with Citrobacter rodentium, which is considered similar to enteropathogenic Escherichia coli infection in humans, macrophage IL-10 was required to prevent intestinal pathology and to promote survival. The synthesis of the proinflammatory cytokine IL-23 was significantly increased in infected mice with a myeloid cell specific deletion of IL-10 and the addition of IL-10 reduced in vitro IL-23 production by intestinal macrophages. Furthermore, blockade of IL-23 led to reduced morbidity and mortality in the context of macrophage IL-10 deficiency. Transcriptome analysis indicated that the reporter positive and negative colonic macrophage subsets were highly similar, but the reporter positive cells differed for the expression of CD163, an IL-10 target gene, suggesting an autocrine IL-10 signal, and when obtained from infected mice, they had reduced IL-23p19 mRNA. Interestingly, only transfer of the reporter positive cells could rescue IL-10 deficient infected mice. Therefore, these data indicate a pivotal role for a subset of intestinal macrophages that constitutively produces IL-10, perhaps acting in part in autocrine fashion, in controlling excessive innate immune activation, regulation of IL-23 production, and prevention of tissue damage after an acute bacterial infection in the intestine. Two replicates each of IL10+ and IL10- large intestinal macrophages. Data were normalized with the 'rma' function of the Bioconductor package, along with several GEO (GSM616132, GSM616136, GSM616140, GSM868296, GSM868297, GSM868298) and ArrayExpress (E-MEXP-3216: 04-M2WT, 05-M2WT, 06-M2WT) datasets.
2015-05-12 | E-GEOD-58677 | biostudies-arrayexpress
Project description:T cell receptor (TCR)-mediated inhibition of interleukin-7 (IL-7) signaling is important for lineage fate determination in the thymus and for T cell survival in the periphery because uninterrupted IL-7 signaling results in T cell death. The initial event in IL-7 signaling is the transactivation of Janus kinases 1 and 3 (Jak1 and Jak3), which are associated with the cytosolic tails of the IL-7 receptor α chain (IL-7Rα) and the γc subunit, the two cell surface proteins that constitute IL-7R. We found that Jak1 is a highly unstable protein with a half-life of only 1.5 hours, so that continuous Jak1 protein synthesis is required to maintain Jak1 protein in sufficient abundance to support IL-7 signaling. However, we also found that Jak1 protein synthesis was acutely reduced by TCR-responsive microRNAs in the miR-17 family, which targeted Jak1 mRNA (messenger RNA) to inhibit its translation. Thus, this study identifies a molecular mechanism by which TCR engagement acutely disrupts IL-7 signaling.
| S-EPMC6679598 | biostudies-literature