Endothelial cells (ECs) are a heterogeneous population that fulfills many physiological processes. ECs also actively participate in both innate and adaptive immune responses. ECs are one of the first ...cell types to detect foreign pathogens and endogenous metabolite-related danger signals in the bloodstream, in which ECs function as danger signal sensors. Treatment with lipopolysaccharide activates ECs, causing the production of pro-inflammatory cytokines and chemokines, which amplify the immune response by recruiting immune cells. Thus, ECs function as immune/inflammation effectors and immune cell mobilizers. ECs also induce cytokine production by immune cells, in which ECs function as immune regulators either by activating or suppressing immune cell function. In addition, under certain conditions, ECs can serve as antigen presenting cells (antigen presenters) by expressing both MHC I and II molecules and presenting endothelial antigens to T cells. These facts along with the new concept of endothelial plasticity suggest that ECs are dynamic cells that respond to extracellular environmental changes and play a meaningful role in immune system function. Based on these novel EC functions, we propose a new paradigm that ECs are conditional innate immune cells. This paradigm provides a novel insight into the functions of ECs in inflammatory/immune pathologies.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
There are multiple sources of reactive oxygen species (ROS) in the cell. As a major site of ROS production, mitochondria have drawn considerable interest because it was recently discovered that ...mitochondrial ROS (mtROS) directly stimulate the production of proinflammatory cytokines and pathological conditions as diverse as malignancies, autoimmune diseases, and cardiovascular diseases all share common phenotype of increased mtROS production above basal levels. Several excellent reviews on this topic have been published, but ever-changing new discoveries mandated a more up-to-date and comprehensive review on this topic. Therefore, we update recent understanding of how mitochondria generate and regulate the production of mtROS and the function of mtROS both in physiological and pathological conditions. In addition, we describe newly developed methods to probe or scavenge mtROS and compare these methods in detail. Thorough understanding of this topic and the application of mtROS-targeting drugs in the research is significant towards development of better therapies to combat inflammatory diseases and inflammatory malignancies.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
It remains unknown whether newly identified anti-inflammatory/immunosuppressive cytokine interleukin-35 (IL-35) is different from other anti-inflammatory cytokines such as IL-10 and transforming ...growth factor (TGF)-β in terms of inhibition of inflammation initiation and suppression of full-blown inflammation. Using experimental database mining and statistical analysis methods we developed, we examined the tissue expression profiles and regulatory mechanisms of IL-35 in comparison to other anti-inflammatory cytokines. Our results suggest that in contrast to TGF-β, IL-35 is not constitutively expressed in human tissues but it is inducible in response to inflammatory stimuli. We also provide structural evidence that AU-rich element (ARE) binding proteins and microRNAs target IL-35 subunit transcripts, by which IL-35 may achieve non-constitutive expression status. Furthermore, we propose a new system to categorize anti-inflammatory cytokines into two groups: (1) the house-keeping cytokines, such as TGF-β, inhibit the initiation of inflammation whereas (2) the responsive cytokines including IL-35 suppress inflammation in full-blown stage. Our in-depth analyses of molecular events that regulate the production of IL-35 as well as the new categorization system of anti-inflammatory cytokines are important for the design of new strategies of immune therapies.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The role of receptors for endogenous metabolic danger signals-associated molecular patterns has been characterized recently as bridging innate immune sensory systems for danger signals-associated ...molecular patterns to initiation of inflammation in bone marrow-derived cells, such as macrophages. However, it remains unknown whether endothelial cells (ECs), the cell type with the largest numbers and the first vessel cell type exposed to circulating danger signals-associated molecular patterns in the blood, can sense hyperlipidemia. This report determined whether caspase-1 plays a role in ECs in sensing hyperlipidemia and promoting EC activation.
Using biochemical, immunologic, pathological, and bone marrow transplantation methods together with the generation of new apoplipoprotein E (ApoE)(-/-)/caspase-1(-/-) double knockout mice, we made the following observations: (1) early hyperlipidemia induced caspase-1 activation in ApoE(-/-) mouse aorta; (2) caspase-1(-/-)/ApoE(-/-) mice attenuated early atherosclerosis; (3) caspase-1(-/-)/ApoE(-/-) mice had decreased aortic expression of proinflammatory cytokines and attenuated aortic monocyte recruitment; and (4) caspase-1(-/-)/ApoE(-/-) mice had decreased EC activation, including reduced adhesion molecule expression and cytokine secretion. Mechanistically, oxidized lipids activated caspase-1 and promoted pyroptosis in ECs by a reactive oxygen species mechanism. Caspase-1 inhibition resulted in accumulation of sirtuin 1 in the ApoE(-/-) aorta, and sirtuin 1 inhibited caspase-1 upregulated genes via activator protein-1 pathway.
Our results demonstrate for the first time that early hyperlipidemia promotes EC activation before monocyte recruitment via a caspase-1-sirtuin 1-activator protein-1 pathway, which provides an important insight into the development of novel therapeutics for blocking caspase-1 activation as early intervention of metabolic cardiovascular diseases and inflammations.
Interleukin-17 (IL-17)-secreting T helper 17 cells were recently identified as a CD4+ T helper subset and implicated in various inflammatory and autoimmune diseases. The issues of whether and by what ...mechanism hyperlipidemic stress induces IL-17A to activate aortic endothelial cells (ECs) and enhance monocyte adhesion remained largely unknown. Using biochemical, immunological, microarray, experimental data mining analysis, and pathological approaches focused on primary human and mouse aortic ECs (HAECs and MAECs) and our newly generated apolipoprotein E (ApoE)−/−/IL-17A−/− mice, we report the following new findings. 1) The hyperlipidemia stimulus oxidized low density lipoprotein up-regulated IL-17 receptor(s) in HAECs and MAECs. 2) IL-17A activated HAECs and increased human monocyte adhesion in vitro. 3) A deficiency of IL-17A reduced leukocyte adhesion to endothelium in vivo. 3) IL-17A activated HAECs and MAECs via up-regulation of proinflammatory cytokines IL-6, granulocyte-macrophage colony-stimulating factor (GM-CSF), chemokine CXC motif ligand 1 (CXCL1), and CXCL2. 4) IL-17A activated ECs specifically via the p38 mitogen-activated protein kinases (MAPK) pathway; the inhibition of p38 MAPK in ECs attenuated IL-17A-mediated activation by ameliorating the expression of the aforementioned proinflammatory cytokines, chemokines, and EC adhesion molecules including intercellular adhesion molecule 1. Taken together, our results demonstrate for the first time that IL-17A activates aortic ECs specifically via p38 MAPK pathway.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
CD4
FOXP3
regulatory T cells (Tregs) are a subset of CD4 T cells that play an essential role in maintaining peripheral immune tolerance, controlling acute and chronic inflammation, allergy, ...autoimmune diseases, and anti-cancer immune responses. Over the past 20 years, significant progress has been made since Tregs were first characterized in 1995. Many concepts and principles regarding Tregs generation, phenotypic features, subsets (tTregs, pTregs, iTregs, and iTreg35), tissue specificity (central Tregs, effector Tregs, and tissue resident Tregs), homeostasis (highly dynamic and apoptotic), regulation of Tregs by receptors for PAMPs and DAMPs, Treg plasticity (re-differentiation to other CD4 T helper cell subsets, Th1, Th2, Tfh and Th17), and epigenetic regulation of Tregs phenotypes and functions have been innovated. In this concise review, we want to briefly analyze these eight new progresses in the study of Tregs. We have also proposed for the first time a novel concept that "physiological Tregs" have been re-shaped into "pathological Tregs" in various pathological environments. Continuing of the improvement in our understanding on this important cellular component about the immune tolerance and immune suppression, would lead to the future development of novel therapeutics approaches for acute and chronic inflammatory diseases, allergy, allogeneic transplantation-related immunity, sepsis, autoimmune diseases, and cancers.
Abstract Objective The preferred amino acids in the proteolytic sites have been considered to be similar between caspase-1 and caspase-9, which do not support their differential functions in ...inflammatory pyroptosis and apoptosis. We attempted to solve this problem. Methods We analyzed the flanking 20 amino acid residues in the cleavage sites in 34 caspase-1 and 11 capase-9 experimentally identified substrates. Results This study has made the following findings: first, we verified that caspase-1 and caspase-9 shared 100% aspartic acid in the P1 position. However, the structures in the cleavage sites of most caspase-1 substrates are different from that of caspase-9 substrates in the following three aspects, (a) the amino acid residues with the statistically high frequencies; (b) the hydrophobic amino acid occurrence frequencies; and (c) the charged amino acid occurrence frequencies; second, the amino acid pairs P1–P1′ are different; third, our identified cleavage site patterns are useful in the prediction for the 91.4% cleavage sites of 35 new caspase-1 substrates. Conclusion Since most caspase-1 substrates are involved in vascular function, inflammation and atherogenesis, our novel structural patterns for the caspases’ substrates are significant in developing new diagnostics and therapeutics.
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GEOZS, IMTLJ, KILJ, KISLJ, NUK, OILJ, SBCE, SBJE, UL, UPCLJ, UPUK
T helper 17 cells (Th17) are a new CD4+ T helper subset that has been implicated in inflammatory and autoimmune diseases. Th17, along with CD4(+)CD25(high) Foxp3(+) regulatory T cells (Tregs) and ...other new T helper subsets, have expanded the Th1-Th2 paradigm. Although this new eight-subset paradigm significantly improved our understanding on the differentiation and regulation of CD4+ T helper subsets, many questions remain to be answered. Here we will briefly review the following issues: a) Old Th1-Th2 paradigm versus new multi-subset paradigm; b) Structural features of IL-17 family cytokines; c) Th17 cells; d) Effects of IL-17 on various cell types and tissues; e) IL-17 receptor and signaling pathways; f) Th17-mediated inflammations; and g) Protective mechanisms of IL-17 in infections. Lastly, we will examine the interactions of Th17 and Treg in autoimmune diseases and inflammation: Th17 cells interplay with Tregs. Regulation of autoimmunity and inflammation lies in the interplays of the different T helper subsets, therefore, better understanding of these subsets' interactions would greatly improve our approaches in developing therapy to combat inflammatory and autoimmune diseases.
Plasma homocysteine (Hcy) levels are positively correlated with cardiovascular mortality in diabetes. However, the joint effect of hyperhomocysteinemia (HHcy) and hyperglycemia (HG) on endothelial ...dysfunction (ED) and the underlying mechanisms have not been studied. Mild (22 µmol/L) and moderate (88 µmol/L) HHcy were induced in cystathionine β-synthase wild-type (Cbs(+/+)) and heterozygous-deficient (Cbs(-/+)) mice by a high-methionine (HM) diet. HG was induced by consecutive injection of streptozotocin. We found that HG worsened HHcy and elevated Hcy levels to 53 and 173 µmol/L in Cbs(+/+) and Cbs(-/+) mice fed an HM diet, respectively. Both mild and moderate HHcy aggravated HG-impaired endothelium-dependent vascular relaxation to acetylcholine, which was completely abolished by endothelial nitric oxide synthase (eNOS) inhibitor N(G)-nitro-L-arginine methyl ester. HHcy potentiated HG-induced calpain activation in aortic endothelial cells isolated from Cbs mice. Calpain inhibitors rescued HHcy- and HHcy/HG-induced ED in vivo and ex vivo. Moderate HHcy- and HG-induced μ-calpain activation was potentiated by a combination of HHcy and HG in the mouse aorta. μ-Calpain small interfering RNA (μ-calpsiRNA) prevented HHcy/HG-induced ED in the mouse aorta and calpain activation in human aortic endothelial cells (HAECs) treated with DL-Hcy (500 µmol/L) and d-glucose (25 mmol) for 48 h. In addition, HHcy accelerated HG-induced superoxide production as determined by dihydroethidium and 3-nitrotyrosin staining and urinary 8-isoprostane/creatinine assay. Antioxidants rescued HHcy/HG-induced ED in mouse aortas and calpain activation in cultured HAECs. Finally, HHcy potentiated HG-suppressed nitric oxide production and eNOS activity in HAECs, which were prevented by calpain inhibitors or μ-calpsiRNA. HHcy aggravated HG-increased phosphorylation of eNOS at threonine 497/495 (eNOS-pThr497/495) in the mouse aorta and HAECs. HHcy/HG-induced eNOS-pThr497/495 was reversed by µ-calpsiRNA and adenoviral transduced dominant negative protein kinase C (PKC)β2 in HAECs. HHcy and HG induced ED, which was potentiated by the combination of HHcy and HG via μ-calpain/PKCβ2 activation-induced eNOS-pThr497/495 and eNOS inactivation.
Obesity paradox (OP) describes a widely observed clinical finding of improved cardiovascular fitness and survival in some overweight or obese patients. The molecular mechanisms underlying OP remain ...enigmatic partly due to a lack of animal models mirroring OP in patients. Using apolipoprotein E knock-out (apoE
) mice on a high fat (HF) diet as an atherosclerotic obesity model, we demonstrated 1) microRNA-155 (miRNA-155, miR-155) is significantly up-regulated in the aortas of apoE
mice, and miR-155 deficiency in apoE
mice inhibits atherosclerosis; 2) apoE
/miR-155
(double knock-out (DKO)) mice show HF diet-induced obesity, adipocyte hypertrophy, and present with non-alcoholic fatty liver disease; 3) DKO mice demonstrate HF diet-induced elevations of plasma leptin, resistin, fed-state and fasting insulin and increased expression of adipogenic transcription factors but lack glucose intolerance and insulin resistance. Our results are the first to present an OP model using DKO mice with features of decreased atherosclerosis, increased obesity, and non-alcoholic fatty liver disease. Our findings suggest the mechanistic role of reduced miR-155 expression in OP and present a new OP working model based on a single miRNA deficiency in diet-induced obese atherogenic mice. Furthermore, our results serve as a breakthrough in understanding the potential mechanism underlying OP and provide a new biomarker and novel therapeutic target for OP-related metabolic diseases.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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