Exendin-4 intervention attenuates atherosclerosis severity by modulating myeloid-derived suppressor cells and inflammatory cytokines in ApoE-/- mice.

OBJECTIVE: To investigate the impact of the glucagon-like peptide-1 (GLP-1) receptor agonist Exendin-4 on the proportion of myeloid-derived suppressor cells (MDSCs) in male ApoE-/- mice, and investigate alterations in the concentrations of inflammatory factors in plasma and spleen tissues and assess their correlation with MDSCs. METHODS: Thirty male ApoE-/- mice were randomly divided into five groups (n = 6 per group): control group (CON), model group (MOD), Exendin-4 intervention group (MOD/Ex-4), Exendin-9-39 intervention group (MOD/Ex-9-39), and Exendin-4 + Exendin-9-39 combined intervention group (MOD/Ex-4 + Ex-9-39). After 4 weeks of drug intervention, changes in aortic plaque were observed using Oil Red O staining and H&E staining. Flow cytometry was employed to detect the content of myeloid-derived suppressor cells (MDSCs) in bone marrow and peripheral blood. ELISA was utilized to measure the concentrations of inflammatory factors in mouse peripheral blood plasma, while RT-qPCR was employed to quantify the expression levels of inflammatory factors in the spleen. Pearson correlation analysis was conducted to assess the relationship between MDSCs and inflammatory factors. RESULTS: Mice in the MOD group had significantly higher body weight compared to the CON group, with a statistically significant difference (P<0.05). Following Exendin-4 intervention, body weight was reduced compared to the MOD group (P<0.05). Additionally, Exendin-4 treatment led to a significant reduction in atherosclerotic plaque compared to the MOD group (P<0.001). After Exendin-4 intervention, the proportion of MDSCs in the bone marrow was higher than in the MOD group (P<0.001), and the proportion of MDSCs in peripheral blood was significantly higher than in the MOD group (P<0.05). Further investigation revealed that Exendin-4 could regulate lipid levels in mice, decreasing concentrations of TG (P<0.01), TC (P<0.0001), and LDL-C (P<0.0001), while increasing HDL-C concentrations (P<0.01). Moreover, after Exendin-4 treatment, the level of the cytokine IL-6 in peripheral plasma was significantly lower compared to the MOD group (P<0.0001), while levels of IL-10 and TGF-ß were significantly higher compared to the MOD group (P<0.0001). In the spleen, levels of the cytokines IL-10 (P<0.0001) and TGF-ß (P<0.001) were significantly increased compared to the MOD group. Pearson correlation analysis showed that the proportion of MDSCs in peripheral blood was positively correlated with IL-10 and TGF-ß levels in both the spleen and peripheral blood. Additionally, the proportion of MDSCs in the bone marrow was positively correlated with IL-10 and TGF-ß levels in the spleen and peripheral blood. CONCLUSION: Exendin-4 alleviates the severity of atherosclerosis. This process may be achieved by promoting the secretion of myeloid-derived suppressor cells (MDSCs) in the bone marrow and peripheral blood of atherosclerotic ApoE-/- mice, regulating the ratio of inflammatory factors in the body, reducing mouse body weight, and lowering blood lipids.

Deciphering the therapeutic potential of Myeloid-Specific JAK2 inhibition in acute respiratory distress syndrome.

Acute respiratory distress syndrome (ARDS) is a life-threatening condition characterized by severe inflammation and pulmonary dysfunction. Despite advancements in critical care, effective pharmacological interventions for ARDS remain elusive. While Janus kinase 2 (JAK2) inhibitors have emerged as an innovative treatment for numerous autoinflammatory diseases, their therapeutic potential in ARDS remains unexplored. In this study, we investigated the contribution of JAK2 and its underlying mechanisms in ARDS utilizing myeloid-specific JAK2 knockout murine models alongside a pharmacological JAK2 inhibitor. Notably, myeloid-specific JAK2 knockout led to a notable attenuation of ARDS induced by intratracheal administration of LPS, accompanied by reduced levels of neutrophils and inflammatory cytokines in bronchoalveolar lavage fluid (BALF) and lung tissue. Intriguingly, the ameliorative effects were abolished upon the depletion of monocyte-derived alveolar macrophages (Mo-AMs) rather than tissue-resident alveolar macrophages (TR-AMs). JAK2 deficiency markedly reversed LPS-induced activation of STAT5 in macrophages. Remarkably, pharmacological JAK2 inhibition using baricitinib failed to substantially alleviate neutrophils infiltration, implying that specific inhibition of JAK2 in Mo-AMs is imperative for ARDS amelioration. Collectively, our data suggest that JAK2 may mitigate ARDS progression through the JAK2 pathway in Mo-AMs, underscoring JAK2 in alveolar macrophages, particularly Mo-AMs, as a promising therapeutic target for ARDS treatment.

Machine-learning-based models assist the prediction of pulmonary embolism in autoimmune diseases: A retrospective, multicenter study.

BACKGROUND: Pulmonary embolism (PE) is a severe and acute cardiovascular syndrome with high mortality among patients with autoimmune inflammatory rheumatic diseases (AIIRDs). Accurate prediction and timely intervention play a pivotal role in enhancing survival rates. However, there is a notable scarcity of practical early prediction and risk assessment systems of PE in patients with AIIRD. METHODS: In the training cohort, 60 AIIRD with PE cases and 180 age-, gender-, and disease-matched AIIRD non-PE cases were identified from 7254 AIIRD cases in Tongji Hospital from 2014 to 2022. Univariable logistic regression (LR) and least absolute shrinkage and selection operator (LASSO) were used to select the clinical features for further training with machine learning (ML) methods, including random forest (RF), support vector machines (SVM), neural network (NN), logistic regression (LR), gradient boosted decision tree (GBDT), classification and regression trees (CART), and C5.0 models. The performances of these models were subsequently validated using a multicenter validation cohort. RESULTS: In the training cohort, 24 and 13 clinical features were selected by univariable LR and LASSO strategies, respectively. The five ML models (RF, SVM, NN, LR, and GBDT) showed promising performances, with an area under the receiver operating characteristic (ROC) curve (AUC) of 0.962-1.000 in the training cohort and 0.969-0.999 in the validation cohort. CART and C5.0 models achieved AUCs of 0.850 and 0.932, respectively, in the training cohort. Using D-dimer as a pre-screening index, the refined C5.0 model achieved an AUC exceeding 0.948 in the training cohort and an AUC above 0.925 in the validation cohort. These results markedly outperformed the use of D-dimer levels alone. CONCLUSION: ML-based models are proven to be precise for predicting the onset of PE in patients with AIIRD exhibiting clinical suspicion of PE. TRIAL REGISTRATION: Chictr.org.cn : ChiCTR2200059599.

Mid1 promotes synovitis in rheumatoid arthritis via ubiquitin-dependent post-translational modification.

INTRODUCTION: Current anti-rheumatic drugs are primarily modulating immune cell activation, yet their effectiveness remained suboptimal. Therefore, novel therapeutics targeting alternative mechanisms, such as synovial activation, is urgently needed. OBJECTIVES: To explore the role of Midline-1 (Mid1) in synovial activation. METHODS: NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice were used to establish a subcutaneous xenograft model. Wild-type C57BL/6, Mid1-/-, Dpp4-/-, and Mid1-/-Dpp4-/- mice were used to establish a collagen-induced arthritis model. Cell viability, cell cycle, qPCR and western blotting analysis were used to detect MH7A proliferation, dipeptidyl peptidase-4 (DPP4) and Mid1 levels. Co-immunoprecipitation and proteomic analysis identified the candidate protein of Mid1 substrates. Ubiquitination assays were used to determine DPP4 ubiquitination status. RESULTS: An increase in Mid1, an E3 ubiquitin ligase, was observed in human RA synovial tissue by GEO dataset analysis, and this elevation was confirmed in a collagen-induced mouse arthritis model. Notably, deletion of Mid1 in a collagen-induced arthritis model completely protected mice from developing arthritis. Subsequent overexpression and knockdown experiments on MH7A, a human synoviocyte cell line, unveiled a previously unrecognized role of Mid1 in synoviocyte proliferation and migration, the key aspects of synovial activation. Co-immunoprecipitation and proteomic analysis identified DPP4 as the most significant candidate of Mid1 substrates. Mechanistically, Mid1 promoted synoviocyte proliferation and migration by inducing ubiquitin-mediated proteasomal degradation of DPP4. DPP4 deficiency led to increased proliferation, migration, and inflammatory cytokine production in MH7A, while reconstitution of DPP4 significantly abolished Mid1-induced augmentation of cell proliferation and activation. Additionally, double knockout model showed that DPP4 deficiency abolished the protective effect of Mid1 defect on arthritis. CONCLUSION: Overall, our findings suggest that the ubiquitination of DPP4 by Mid1 promotes synovial cell proliferation and invasion, exacerbating synovitis in RA. These results reveal a novel mechanism that controls synovial activation, positioning Mid1 as a promising target for therapeutic intervention in RA.

Precision Medicine in Rheumatic Diseases: Unlocking the Potential of Antibody-Drug Conjugates.

In the era of precision medicine, antibody-drug conjugates (ADCs) have emerged as a cutting-edge therapeutic strategy. These innovative compounds combine the precision of monoclonal antibodies with the potent cell-killing or immune-modulating abilities of attached drug payloads. This unique strategy not only reduces off-target toxicity but also enhances the therapeutic effectiveness of drugs. Beyond their well established role in oncology, ADCs are now showing promising potential in addressing the unmet needs in the therapeutics of rheumatic diseases. Rheumatic diseases, a diverse group of chronic autoimmune diseases with varying etiologies, clinical presentations, and prognoses, often demand prolonged pharmacological interventions, creating a pressing need for novel, efficient, and low-risk treatment options. ADCs, with their ability to precisely target the immune components, have emerged as a novel therapeutic strategy in this context. This review will provide an overview of the core components and mechanisms behind ADCs, a summary of the latest clinical trials of ADCs for the treatment of rheumatic diseases, and a discussion of the challenges and future prospects faced by the development of next-generation ADCs. SIGNIFICANCE STATEMENT: There is a lack of efficient and low-risk targeted therapeutics for rheumatic diseases. Antibody-drug conjugates, a class of cutting-edge therapeutic drugs, have emerged as a promising targeted therapeutic strategy for rheumatic disease. Although there is limited literature summarizing the progress of antibody-drug conjugates in the field of rheumatic disease, updating the advancements in this area provides novel insights into the development of novel antirheumatic drugs.

HMGB1/RAGE axis in tumor development: unraveling its significance.

High mobility group protein 1 (HMGB1) plays a complex role in tumor biology. When released into the extracellular space, it binds to the receptor for advanced glycation end products (RAGE) located on the cell membrane, playing an important role in tumor development by regulating a number of biological processes and signal pathways. In this review, we outline the multifaceted functions of the HMGB1/RAGE axis, which encompasses tumor cell proliferation, apoptosis, autophagy, metastasis, and angiogenesis. This axis is instrumental in tumor progression, promoting tumor cell proliferation, autophagy, metastasis, and angiogenesis while inhibiting apoptosis, through pivotal signaling pathways, including MAPK, NF-κB, PI3K/AKT, ERK, and STAT3. Notably, small molecules, such as miRNA-218, ethyl pyruvate (EP), and glycyrrhizin exhibit the ability to inhibit the HMGB1/RAGE axis, restraining tumor development. Therefore, a deeper understanding of the mechanisms of the HMGB1/RAGE axis in tumors is of great importance, and the development of inhibitors targeting this axis warrants further exploration.

Midline-1 regulates effector T cell motility in experimental autoimmune encephalomyelitis via mTOR/microtubule pathway.

Background: Effector T cell activation, migration, and proinflammatory cytokine production are crucial steps in autoimmune disorders such as multiple sclerosis (MS). While several therapeutic approaches targeting T cell activation and proinflammatory cytokines have been developed for the treatment of autoimmune diseases, there are no therapeutic agents targeting the migration of effector T cells, largely due to our limited understanding of regulatory mechanisms of T cell migration in autoimmune disease. Here we reported that midline-1 (Mid1) is a key regulator of effector T cell migration in experimental autoimmune encephalomyelitis (EAE), a widely used animal model of MS. Methods: Mid1-/- mice were generated by Crispr-Cas9 technology. T cell-specific Mid1 knockout chimeric mice were generated by adoptive transfer of Mid1-/- T cells into lymphocyte deficient Rag2-/- mice. Mice were either immunized with MOG35-55 (active EAE) or received adoptive transfer of pathogenic T cells (passive EAE) to induce EAE. In vitro Transwell® assay or in vivo footpad injection were used to assess the migration of T cells. Results: Mid1 was significantly increased in the spinal cord of wild-type (Wt) EAE mice and disruption of Mid1 in T cells markedly suppressed the development of both active and passive EAE. Transcriptomic and flow cytometric analyses revealed a marked reduction in effector T cell number in the central nervous system of Mid1-/- mice after EAE induction. Conversely, an increase in the number of T cells was observed in the draining lymph nodes of Mid1-/- mice. Mice that were adoptively transferred with pathogenic Mid1-/- T cells also exhibited milder symptoms of EAE, along with a lower T cell count in the spinal cord. Additionally, disruption of Mid1 significantly inhibited T-cell migration both in vivo and in vitro. RNA sequencing suggests a suppression in multiple inflammatory pathways in Mid1-/- mice, including mTOR signaling that plays a critical role in cell migration. Subsequent experiments confirmed the interaction between Mid1 and mTOR. Suppression of mTOR with rapamycin or microtubule spindle formation with colcemid blunted the regulatory effect of Mid1 on T cell migration. In addition, mTOR agonists MHY1485 and 3BDO restored the migratory deficit caused by Mid1 depletion. Conclusion: Our data suggests that Mid1 regulates effector T cell migration to the central nervous system via mTOR/microtubule pathway in EAE, and thus may serve as a potential therapeutic target for the treatment of MS.

Immunomodulatory effects of iTr35 cell subpopulation and its research progress.

The spotlight in recent years has increasingly focused on inducible regulatory T cells 35 (iTr35), a novel subpopulation of regulatory T cells characterized by phenotypic stability, heightened reactivity, and potent immunosuppressive function through the production of IL-35. Despite being in the exploratory phase, research on iTr35 has garnered significant interest. In this review, we aim to consolidate our understanding of the biological characteristics and immunomodulatory mechanisms of iTr35, offering fresh perspectives that may pave the way for its potential applications in disease diagnosis and treatment.

A comparative study on the clinical and magnetic resonance imaging features between seronegative and seropositive rheumatoid arthritis.

OBJECTIVES: Seronegative rheumatoid arthritis (SNRA) is less common and less known compared with seropositive rheumatoid arthritis (SPRA). The aim of this study was to characterise the clinical and magnetic resonance imaging (MRI) features of SNRA and investigate the associated factors of structural damage. METHODS: We retrospectively collected newly diagnosed RA patients who had MRI data of the hands at baseline. The clinical and MRI features and treatment responses during the 12-month follow-up were compared between SNRA and SPRA. The associated factors of the erosion rate were analysed. RESULTS: A total of 310 RA patients were included in this study. Compared with SPRA, SNRA had a higher level of inflammation (p-values were all <0.001), a higher incidence of low bone mineral density (p=0.009), but a lower erosion score (p<0.001) and a lower probability of interstitial lung disease (ILD) (p=0.019). The main eroded bones were different between SNRA (the scaphoid and the lunate) and SPRA (the capitate and the hamate). In the multivariate analysis, synovitis score, the levels of IL-6 and TNF-α, and hyperglobulinaemia were positively associated with the erosion rate of SNRA (p-values were all <0.05). During the 12-month follow-up, the treatment response between the two groups was comparable (p-values were all >0.05). CONCLUSIONS: SNRA had more severe inflammation but milder erosion compared with SPRA. SNRA with severe inflammation or hyperglobulinaemia needs the same powerful therapy of SPRA to prevent erosion progression.

Aberrant follicular regulatory T cells associate with immunoglobulin hyperproduction in nasal polyps with ectopic lymphoid tissues.

BACKGROUND: Ectopic lymphoid tissues (eLTs) and associated follicular helper T (TFH) cells contribute to local immunoglobulin hyperproduction in nasal polyps (NPs). Follicular regulatory T (TFR) cells in secondary lymphoid organs counteract TFH cells and suppress immunoglobulin production; however, the presence and function of TFR cells in eLTs in peripheral diseased tissues remain poorly understood. OBJECTIVE: We sought to investigate the presence, phenotype, and function of TFR cells in NPs. METHODS: The presence, abundance, and phenotype of TFR cells in NPs were examined using single-cell RNA sequencing, immunofluorescence staining, and flow cytometry. Sorted polyp and circulating T-cell subsets were cocultured with autologous circulating naïve B cells, and cytokine and immunoglobulin production were measured by ELISA. RESULTS: TFR cells were primarily localized within eLTs in NPs. TFR cell frequency and TFR cell/TFH cell ratio were decreased in NPs with eLTs compared with NPs without eLTs and control inferior turbinate tissues. TFR cells displayed an overlapping phenotype with TFH cells and FOXP3+ regulatory T cells in NPs. Polyp TFR cells had reduced CTLA-4 expression and decreased capacity to inhibit TFH cell-induced immunoglobulin production compared with their counterpart in blood and tonsils. Blocking CTLA-4 abolished the suppressive effect of TFR cells. Lower vitamin D receptor expression was observed on polyp TFR cells compared with TFR cells in blood and tonsils. Vitamin D treatment upregulated CTLA-4 expression on polyp TFR cells and restored their suppressive function in vitro. CONCLUSIONS: Polyp TFR cells in eLTs have decreased CLTA-4 and vitamin D receptor expression and impaired capacity to suppress TFH cell-induced immunoglobulin production, which can be reversed by vitamin D treatment in vitro.

The Role of the IL-33/ST2 Axis in CpG-Induced Macrophage Activation Syndrome.

Background: Macrophage activation syndrome (MAS) is a fatal inflammatory condition, which is often associated with the elevation of multiple proinflammatory cytokines and multiple organ dysfunction. Previous studies have shown that ST2 contributes to T cell overactivation and plays a detrimental role in mouse models of primary hemophagocytic lymphohistiocytosis. The purpose of this study was to investigate the role of the IL-33/ST2 axis in a mouse model of MAS induced by repeated injections of cytosine-phosphate-guanine (CpG). Methods: Serum cytokines were determined using the cytometric bead array by flow cytometry. IL-33 and ST2 were detected by immunohistochemistry and real-time quantitative PCR in the liver and spleen of mice. CD3 and F4/80 in the liver were detected by immunohistochemistry. Inflammatory macrophages and effector memory T lymphocytes were detected by flow cytometry. Result: The CpG-induced MAS model was successfully induced after repeated CpG injections, presenting with hypercytokinemia and hepatosplenomegaly. The numbers of IL-33 positive cells in the liver and spleen decreased significantly, while the expression of ST2 in the liver tended to increase in the mice with MAS. IL-33 and St2 knockout mice showed similar levels of hepatosplenomegaly, peripheral blood count, and cytokine storm when compared with wild-type (WT) mice after induction of MAS. There were also no significant differences in liver pathology (including inflammatory cell infiltration of CD3 and F4/80) and levels of splenic inflammatory macrophages and effector memory T cells between the WT and knockout mice. Conclusion: These results suggested that IL-33 decreased in the liver and spleen tissues of MAS mice. Further results suggest that IL-33 and St2 knockout mice have no treatment potential in CpG-induced MAS. Thus, the IL-33/ST2 axis has little effect on the prognosis of CpG-induced MAS.

Linggui Zhugan decoction delays ventricular remodeling in rats with chronic heart failure after myocardial infarction through the Wnt/ß-catenin signaling pathway.

CONTEXT: Traditional Chinese medicine plays an important role in the prevention and treatment of heart failure (HF). Linggui Zhugan decoction has been approved for clinical treatment of chronic HF. However, the mechanism is still unclear. OBJECTIVE: The effect of Linggui Zhugan decoction on the Wnt/ß-catenin signaling pathway in rat myocardium was studied to investigate the mechanism by Linggui Zhugan decoction effects ventricular remodeling in rats with heart failure after myocardial infarction. METHOD: A rat model of HF after myocardial infarction was prepared by ligating the left anterior descending coronary artery. After 6 weeks of intervention with Linggui Zhugan decoction, the effect of Linggui Zhugan decoction on the cardiac function of chronic HF model rats was observed. Myocardial infarct size was measured by triphenyl tetrazolium chloride (TTC) staining. Enzyme linked immunosorbent assays (ELISAs) were used to measure NT-proBNP and sST-2 concentrations in rat serum. Hematoxylin and eosin (H&E) staining, and Masson's trichrome staining were used to observe the morphology of myocardial tissue; immunohistochemistry was used to detect the protein expression of type I collagen and type III collagen in myocardial tissue; and mRNA expression levels of Wnt3a, GSK-3ß, ß-catenin, and c-Myc in the infarct marginal zone were detected using PCR. Protein expression of Wnt3a, p-GSK-3ß, GSK-3ß, and ß-catenin in the infarct marginal zone was detected using western blot. RESULTS: Compared with the control, Linggui Zhugan decoction reduced the levels of serum ST-2 and NT-proBNP, improved cardiac function, and reduced the deposition of collagen fiber. In addition, Linggui Zhugan decoction inhibited the expression of Wnt3a, p-GSK-3ß, and ß-catenin in cardiomyocytes. CONCLUSION: Linggui Zhugan decoction inhibits the expression of several key proteins in the Wnt/ß-catenin signaling pathway, delays cardiomyocyte hypertrophy and fibrosis, and improves cardiac function.

JAK2/STAT5 inhibition protects mice from experimental autoimmune encephalomyelitis by modulating T cell polarization.

Multiple sclerosis (MS) has been considered as a T cell-mediated autoimmune disease. However, the signaling pathways regulating effector T cells in MS have yet to be elucidated. Janus kinase 2 (JAK2) plays a crucial role in hematopoietic/immune cytokine receptor signal transduction. Here, we tested the mechanistic regulation of JAK2 and the therapeutic potential of pharmacological JAK2 inhibition in MS. Both inducible whole-body JAK2 knockout and T cell-specific JAK2 knockout completely prevented the onset of experimental autoimmune encephalomyelitis (EAE), a widely used MS animal model. Mice with JAK2 deficiency in T cells exhibited minimal demyelination and minimal CD45+ leukocyte infiltration in the spinal cord, accompanied by a remarkable reduction of T helper cell type 1 (TH1) and type 17 (TH17) in the draining lymph nodes and spinal cord. In vitro experiments showed that disruption of JAK2 markedly suppressed TH1 differentiation and IFNγ production. The phosphorylation of signal transducer and activator of transcription 5 (STAT5) was reduced in JAK2 deficient T cells, while STAT5 overexpression significantly increased TH1 and IFNγ production in STAT5 transgenic mice. Consistent with these results, JAK1/2 inhibitor baricitinib or selective JAK2 inhibitor fedratinib attenuated the frequencies of TH1 as well as TH17 in the draining lymph nodes and alleviated the EAE disease activity in mice. Our findings suggest that overactive JAK2 signaling in T lymphocytes is the culprit in EAE, which may serve as a potent therapeutic target for autoimmune disease.

Linggui Zhugan Decoction activates the SIRT1-AMPK-PGC1α signaling pathway to improve mitochondrial and oxidative damage in rats with chronic heart failure caused by myocardial infarction.

Objective: To investigate the effects of Linggui Zhugan Decoction on mitochondrial and oxidative damage in rats with chronic heart failure after myocardial infarction and the related mechanisms. Methods: Chronic heart failure after myocardial infarction was established by coronary artery ligation. Heart failure rats were randomly divided into three groups: Model group (n = 11), Linggui Zhugan Decoction group (n = 12), and captopril group (n = 11). Rats whose coronary arteries were only threaded and not ligated were sham group (n = 11). Cardiac function, superoxide dismutase (SOD), malondialdehyde (MDA) contents, soluble growth-stimulating expression factor (ST2), and N-terminal B-type brain natriuretic peptide precursor (NTproBNP) levels were analyzed after treatment. Moreover, the level of mitochondrial membrane potential was detected by JC-1 staining, the ultrastructural of myocardial mitochondria were observed by transmission electron microscopy. The related signal pathway of silent information regulator factor 2-related enzyme 1 (SIRT1), adenylate activated protein kinase (AMPK), phosphorylated adenylate activated protein kinase (p-AMPK), and peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) is an important pathway to regulate mitochondrial energy metabolism, and to initiate mitochondrial biogenesis. The expression level was detected by Western blot and reverse transcription to explore the mechanism of the decoction. Results: Compared with the model rats, Linggui Zhugan Decoction significantly improved cardiac function (p < 0.05), reduced MDA production (p < 0.01), increased SOD activity (p < 0.05), reduced ST-2(p < 0.01), and NT-proBNP(p < 0.05) levels, increased mitochondrial membrane potential, and improved mitochondria function. In addition, Linggui Zhugan Decoction upregulated the expression of SIRT1, p-AMPK, PGC-1α protein, and mRNA in cardiac myocytes. Conclusion: Linggui Zhugan Decoction can improve the cardiac function of heart failure rats by enhancing myocardial antioxidant capacity and protecting the mitochondrial function, the mechanism is related to activating SIRT1/AMPK/PGC-1α signaling pathway.

Particulate air pollution exaggerates diet-induced insulin resistance through NLRP3 inflammasome in mice.

Air particulate matter 2.5 (PM2.5) has been demonstrated to exaggerate insulin resistance in both human and animal studies. However, the exact molecular mechanisms remain elusive. This study sought to assess the role of NLRP3 inflammasome in PM2.5 exposure-induced insulin resistance and explore the underlying mechanisms. Wild-type (WT), Nlrp3-/-, Tlr4Lps-d, or Nrf2-/- mice, on a normal diet or high-fat diet (HFD), were exposed to PM2.5 or filtered air (FA) in a whole-body exposure facility. Priming (first signal) and assembly (second signal) of NLRP3 inflammasome activation were assessed by measuring the transcription of Nlrp3/Il-1ß and detecting the activity of caspase-1 and secretion of IL-1ß. We found PM2.5 exposure exaggerated insulin resistance and increased IL-1ß production in the HFD-fed WT mice, but not Nlrp3-/- mice. Gene expressions of Nlrp3 and Il-1ß in the lungs and peritoneal macrophages were upregulated in WT mice exposed to PM2.5. When stimulated with LPS (first signal) or monosodium urate (second signal), PM2.5 exposure was able to enhance the activity of caspase-1 and IL-1ß secretion, suggesting that PM2.5 may serve as a stimulus of either the first or second signal for NLRP3 inflammasome activation. Effects of PM2.5 on caspase-1 activation and IL-1ß secretion were partially blocked in Tlr4Lps-d mice. Reactive oxygen species (ROS), co-localization of NLRP3 and mitochondria, and secondary lysosomes in macrophages were increased after PM2.5 exposure, while deficiency of antioxidant gene Nrf2 in mice significantly enhanced PM2.5-induced secretion of IL-1ß. Imaging flow cytometry and transmission electron microscopy demonstrated an engulfment of PM2.5 particles by macrophages, while suppression of phagocytosis by cytochalasin D abolished PM2.5-induced transcription of Nlrp3/Il-1ß. Our results demonstrated a critical role of NLRP3 inflammasome in PM2.5 exaggerated insulin resistance, and multiple pathways in the first and second signals of NLRP3 inflammasome activation may be involved.

Perturbated glucose metabolism augments epithelial cell proinflammatory function in chronic rhinosinusitis.

BACKGROUND: Glucose concentrations are increased in nasal secretions in chronic rhinosinusitis (CRS). However, the glucose metabolism and its contribution to disease pathogenesis in CRS remain unexplored. OBJECTIVES: We sought to explore the glucose metabolism and its effect on the function of nasal epithelial cells in CRS with and without nasal polyps (CRSwNP and CRSsNP). METHODS: Glucose metabolites were detected with mass spectrometry. The mRNA levels of glucose transporters (GLUTs), metabolic enzymes, and inflammatory mediators were detected by quantitative RT-PCR. The protein expression of GLUTs was studied by immunofluorescence staining, Western blotting, and flow cytometry. Glucose uptake was measured by using fluorescent glucose analog. Human nasal epithelial cells (HNECs) were cultured. Bioenergetic analysis was performed with Seahorse XF analyzer. Gene expression in HNECs was profiled by RNA sequencing. RESULTS: Increased glucose concentrations in nasal secretions was confirmed in both CRSsNP and CRSwNP. GLUT4, GLUT10, and GLUT11 were abundantly expressed in HNECs, whose expression was upregulated by inflammatory cytokines and D-glucose and was increased in CRS. Glucose uptake, glycolysis and tricarboxylic acid cycle metabolites, metabolic enzymes, and extracellular acidification rate and oxygen consumption rates were increased in HNECs in CRSsNP and CRSwNP, with a predominant shift to glycolysis. HNECs treated with high-level apical D-glucose showed enhanced glucose uptake, predominant glycolysis, and upregulated production of IL-1α, IL-1ß, TNF-α, CCL20, and CXCL8, which was suppressed by 2-deoxy-D-glucose, an inhibitor of glycolysis. CONCLUSIONS: Increased glucose in nasal secretions promotes glucose uptake and predominant glycolysis in epithelial cells, augmenting the proinflammatory function of epithelial cells in CRS.

The role of myeloid-derived immunosuppressive cells in cardiovascular disease.

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous cell population found in the bone marrow, peripheral blood, and tumor tissue. Their role is mainly to inhibit the monitoring function of innate and adaptive immune cells, which leads to the escape of tumor cells and promotes tumor development and metastasis. Moreover, recent studies have found that MDSCs are therapeutic in several autoimmune disorders due to their strong immunosuppressive ability. Additionally, studies have found that MDSCs have an important role in the formation and progression of other cardiovascular diseases, such as atherosclerosis, acute coronary syndrome, and hypertension. In this review, we will discuss the role of MDSCs in the pathogenesis and treatment of cardiovascular disease.

Regulatory T cells: a new therapeutic link for Sjögren syndrome?

Great advancements have been made in understanding the pathogenesis of SS, but there remain unmet needs for effective and targeted treatments. Glandular and extraglandular dysfunction in SS is associated with autoimmune lymphocytic infiltration that invades the epithelial structures of affected organs. Regulatory T (Treg) cells are a subset of CD4+ T lymphocytes that maintain self-tolerance during physiological conditions. Besides inhibiting excessive inflammation and autoimmune response by targeting various immune cell subsets and tissues, Treg cells have also been shown to promote tissue repair and regeneration in pathogenic milieus. The changes of quantity and function of Treg cells in various autoimmune and chronic inflammatory disorders have been reported, owing to their effects on immune regulation. Here we summarize the recent findings from murine models and clinical data about the dysfunction of Treg cells in SS pathogenesis and discuss the therapeutic strategies of direct or indirect targeting of Treg cells in SS. Understanding the current knowledge of Treg cells in the development of SS will be important to elucidate disease pathogenesis and may guide research for successful therapeutic intervention in this disease.

Dipeptidyl Peptidase 4/Midline-1 Axis Promotes T Lymphocyte Motility in Atherosclerosis.

T cells play a crucial role in atherosclerosis, with its infiltration preceding the formation of atheroma. However, how T-cell infiltration is regulated in atherosclerosis remains largely unknown. Here, this work demonstrates that dipeptidyl peptidase-4 (DPP4) is a novel regulator of T-cell motility in atherosclerosis. Single-cell ribonucleic acid (RNA) sequencing and flow cytometry show that CD4+ T cells in atherosclerotic patients display a marked increase of DPP4. Lack of DPP4 in hematopoietic cells or T cells reduces T-cell infiltration and atherosclerotic plaque volume in atherosclerosis mouse models. Mechanistically, DPP4 deficiency reduces T-cell motility by suppressing the expression of microtubule associated protein midline-1 (Mid1) in T cells. Deletion of either DPP4 or Mid1 inhibits chemokine-induced shape change and motility, while restitution of Mid1 in Dpp4-/- T cell largely restores its migratory ability. Thus, DPP4/Mid1, as a novel regulator of T-cell motility, may be a potential inflammatory target in atherosclerosis.