RESUMEN
The article delves into the pathogenesis of systemic sclerosis (SSc) with an emphasis on immunometabolism dysfunctions. SSc is a complex autoimmune connective tissue disorder with skin and organ fibrosis manifestation, vasculopathy, and immune dysregulation. A growing amount of research indicates that immunometabolism plays a significant role in the pathogenesis of autoimmune diseases, including SSc. The review explores the intricate interplay between immune dysfunction and metabolic alterations, focusing on the metabolism of glucose, lipids, amino acids, the TCA (tricarboxylic acid) cycle, and oxidative stress in SSc disease. According to recent research, there are changes in various metabolic pathways that could trigger or perpetuate the SSc disease. Glycolysis and TCA pathways play a pivotal role in SSc pathogenesis through inducing fibrosis. Dysregulated fatty acid ß-oxidation (FAO) and consequent lipid metabolism result in dysregulated extracellular matrix (ECM) breakdown and fibrosis induction. The altered metabolism of amino acids can significantly be involved in SSc pathogenesis through various mechanisms. Reactive oxygen species (ROS) production has a crucial role in tissue damage in SSc patients. Indeed, immunometabolism involvement in SSc is highlighted, which offers potential therapeutic avenues. The article underscores the need for comprehensive studies to unravel the multifaceted mechanisms driving SSc pathogenesis and progression.
RESUMEN
Micro RNAs (miRNAs, miRs) and relevant networks might exert crucial functions during differential host cell infection by the different Leishmania species. Thus, a bioinformatic analysis of microarray datasets was developed to identify pivotal shared biomarkers and miRNA-based regulatory networks for Leishmaniasis. A transcriptomic analysis by employing a comprehensive set of gene expression profiling microarrays was conducted to identify the key genes and miRNAs relevant for Leishmania spp. infections. Accordingly, the gene expression profiles of healthy human controls were compared with those of individuals infected with Leishmania mexicana, L. major, L. donovani, and L. braziliensis. The enrichment analysis for datasets was conducted by utilizing EnrichR database, and Protein-Protein Interaction (PPI) network to identify the hub genes. The prognostic value of hub genes was assessed by using receiver operating characteristic (ROC) curves. Finally, the miRNAs that interact with the hub genes were identified using miRTarBase, miRWalk, TargetScan, and miRNet. Differentially expressed genes were identified between the groups compared in this study. These genes were significantly enriched in inflammatory responses, cytokine-mediated signaling pathways and granulocyte and neutrophil chemotaxis responses. The identification of hub genes of recruited datasets suggested that TNF, SOCS3, JUN, TNFAIP3, and CXCL9 may serve as potential infection biomarkers and could deserve value as prognostic biomarkers for leishmaniasis. Additionally, inferred data from miRWalk revealed a significant degree of interaction of a number of miRNAs (hsa-miR-8085, hsa-miR-4673, hsa-miR-4743-3p, hsa-miR-892c-3p, hsa-miR-4644, hsa-miR-671-5p, hsa-miR-7106-5p, hsa-miR-4267, hsa-miR-5196-5p, and hsa-miR-4252) with the majority of the hub genes, suggesting such miRNAs play a crucial role afterwards parasite infection. The hub genes and hub miRNAs identified in this study could be potentially suggested as therapeutic targets or biomarkers for the management of leishmaniasis.
Asunto(s)
Biomarcadores , Biología Computacional , Perfilación de la Expresión Génica , Redes Reguladoras de Genes , Leishmaniasis , MicroARNs , Mapas de Interacción de Proteínas , Humanos , MicroARNs/genética , MicroARNs/metabolismo , Leishmaniasis/genética , Leishmaniasis/parasitología , Biología Computacional/métodos , Biomarcadores/metabolismo , Perfilación de la Expresión Génica/métodos , Mapas de Interacción de Proteínas/genética , Transcriptoma , Leishmania/genéticaRESUMEN
BACKGROUND: Fibroblast-like synoviocytes (FLSs) are involved in osteoarthritis (OA) pathogenesis through pro-inflammatory cytokine production. TAK-242, a TLR4 blocker, has been found to have a significant impact on the gene expression profile of pro-inflammatory cytokines such as IL1-ß, IL-6, TNF-α, and TLR4, as well as the phosphorylation of Ikßα, a regulator of the NF-κB signaling pathway, in OA-FLSs. This study aims to investigate this effect because TLR4 plays a crucial role in inflammatory responses. MATERIALS AND METHODS: Ten OA patients' synovial tissues were acquired, and isolated FLSs were cultured in DMEM in order to assess the effectiveness of TAK-242. The treated FLSs with TAK-242 and Lipopolysaccharides (LPS) were analyzed for the mRNA expression level of IL1-ß, IL-6, TNF-α, and TLR4 levels by Real-Time PCR. Besides, we used western blot to assess the protein levels of Ikßα and pIkßα. RESULTS: The results represented that TAK-242 effectively suppressed the gene expression of inflammatory cytokines IL1-ß, IL-6, TNF-α, and TLR4 which were overexpressed upon LPS treatment. Additionally, TAK-242 inhibited the phosphorylation of Ikßα which was increased by LPS treatment. CONCLUSION: According to our results, TAK-242 shows promising inhibitory effects on TLR4-mediated inflammatory responses in OA-FLSs by targeting the NF-κB pathway. TLR4 inhibitors, such as TAK-242, may be useful therapeutic agents to reduce inflammation and its associated complications in OA patients, since traditional and biological treatments may not be adequate for all of them.
Asunto(s)
Citocinas , Interleucina-1beta , Interleucina-6 , Lipopolisacáridos , FN-kappa B , Transducción de Señal , Sulfonamidas , Sinoviocitos , Receptor Toll-Like 4 , Factor de Necrosis Tumoral alfa , Humanos , Transducción de Señal/efectos de los fármacos , Sinoviocitos/efectos de los fármacos , Sinoviocitos/metabolismo , FN-kappa B/metabolismo , Sulfonamidas/farmacología , Sulfonamidas/uso terapéutico , Receptor Toll-Like 4/metabolismo , Citocinas/metabolismo , Interleucina-6/metabolismo , Interleucina-1beta/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Lipopolisacáridos/farmacología , Fibroblastos/metabolismo , Fibroblastos/efectos de los fármacos , Osteoartritis/metabolismo , Osteoartritis/tratamiento farmacológico , Células Cultivadas , Fosforilación , ARN Mensajero/metabolismo , Masculino , Femenino , Persona de Mediana EdadRESUMEN
BACKGROUND: Several studies have demonstrated the improvement in serum lipoproteins by statins in patients with Chronic Kidney Diseases (CKDs), including End-Stage Renal Disease (ESRD). However, the results of these studies are inconclusive. AIM: We aimed to systematically investigate the effect of statins on lipid profiles of patients with CKD by performing a meta-analysis of Randomized Controlled Trials (RCTs). METHODS: Major electronic databases (Scopus, MEDLINE/PubMed, and ISI Web of Science) were searched from inception to August, 2023, to find randomized controlled trials (RCTs) evaluating the effect of different statins on serum lipoproteins in CKD patients. Weighted Mean Difference (WMD) with 95% Confidence Intervals (CI) was used to estimate the effect size. Trial Sequential Analysis (TSA) was performed to confirm the robustness of the evidence. RESULTS: A total of 18 publications were identified. It was found that statins reduced serum levels of Low-Density Lipoprotein (LDL)-C (WMD = -27.81 mg/dl, 95% CI = -34.47 to -21.15, P < 0.001) and total cholesterol (WMD = -25.44 mg/dl, 95% CI = -34.71 to -16.18, P < 0.001) in patients with CKD compared to the control group. Nonetheless, the effect of statins on High-Density Lipoprotein (HDL)-C (WMD = 0.57 mg/dl, 95% CI = -0.71 to 1.85, P = 0.38) and Triglyceride (TG) (WMD = -9.08 mg/dl, 95% CI = -22.22 to 2.06, P = 0.11) was not statistically significant. The results of TSA confirmed the robustness of the evidence and were consistent with the pooled effect size. The findings of subgroup analysis and time response analysis were also significant. CONCLUSION: It was found that statin therapy reduced the levels of LDL-C and total cholesterol in patients with CKD.
Asunto(s)
Inhibidores de Hidroximetilglutaril-CoA Reductasas , Ensayos Clínicos Controlados Aleatorios como Asunto , Insuficiencia Renal Crónica , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Insuficiencia Renal Crónica/tratamiento farmacológico , Insuficiencia Renal Crónica/sangre , Lípidos/sangreRESUMEN
Evidence demonstrates that T cells are implicated in developing SLE, and each of them dominantly uses distinct metabolic pathways. Indeed, intracellular enzymes and availability of specific nutrients orchestrate fate of T cells and lead to differentiation of regulatory T cells (Treg), memory T cells, helper T cells, and effector T cells. The function of T cells in inflammatory and autoimmune responses is determined by metabolic processes and activity of their enzymes. Several studies were conducted to determine metabolic abnormalities in SLE patients and clarify how these modifications could control the functions of the involved T cells. Metabolic pathways such as glycolysis, mitochondrial pathways, oxidative stress, mTOR pathway, fatty acid and amino acid metabolisms are dysregulated in SLE T cells. Moreover, immunosuppressive drugs used in treating autoimmune diseases, including SLE, could affect immunometabolism. Developing drugs to regulate autoreactive T cell metabolism could be a promising therapeutic approach for SLE treatment. Accordingly, increased knowledge about metabolic processes paves the way to understanding SLE pathogenesis better and introduces novel therapeutic options for SLE treatment. Although monotherapy with metabolic pathways modulators might not be sufficient to prevent autoimmune disease, they may be an ideal adjuvant to reduce administration doses of immunosuppressive drugs, thus reducing drug-associated adverse effects. This review summarized emerging data about T cells that are involved in SLE pathogenesis, focusing on immunometabolism dysregulation and how these modifications could affect the disease development.
Asunto(s)
Enfermedades Autoinmunes , Lupus Eritematoso Sistémico , Enfermedades de la Piel , Humanos , Linfocitos T Colaboradores-Inductores , Linfocitos T Reguladores , Estrés Oxidativo , InmunosupresoresRESUMEN
BACKGROUND: Asthma is considered to be a chronic inflammatory disorder of the airways. Probiotics are living microorganisms that are found in the human gut and have protective effects against a wide range of diseases such as allergies. The aim of this study was to investigate the improvement of clinical asthma symptoms and changes in the expression pattern of selective microRNAs in patients with asthma and the changes in IL-4 and IFN-γ plasma levels after receiving probiotics. MATERIALS AND METHODS: The present study was a randomized, double-blind, placebo-controlled trial that enrolled 40 asthmatic patients. They were treated with probiotics or placebo: 1 capsule/day for 8 weeks. Pulmonary function tests, IL-4 and IFN-γ levels, and expression of microRNAs were assessed at baseline and after treatment. RESULTS: The results showed that the expression of miR-16, miR146-a and IL-4 levels in patients with asthma after receiving probiotic supplementation was significantly reduced and miR-133b expression was increased. In addition, pulmonary function tests showed a significant improvement in Forced Expiratory Volume in 1 s and Forced Vital Capacity after receiving probiotics. CONCLUSION: In our study, 8-week treatment with probiotic supplementation led to reduced Th2 cells-associated IL-4 and improved Forced Expiratory Volume and Forced Vital Capacity. It appears probiotics can be used in addition to common asthma treatments.
RESUMEN
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial hyperplasia and joint damage. Systemic complications and progressive disability are burdens that lead to a significant socio-economic costs in patients with RA. Current RA biomarkers used in predicting, diagnosing, and monitoring the treatment of the disease have not been very successful. Moreover, only 60% of patients show a satisfactory response to current biological and conventional therapies. Studies on immunometabolism have suggested that dysregulated enzymes, transcription factors, metabolites, and metabolic pathways could be considered potential therapeutic targets for the treatment of RA. Factors such as the high concentration of various intermediate molecules arising from metabolism, hypoxia, lack of nutrients, and other metabolic alterations affect local immune responses and preserve a state of chronic inflammation in synovial tissues. Fortunately, in vitro and in vivo studies have shown that targeting specific metabolic pathways is associated with a decreased level of inflammation. Specifically, targeting metabolic intermediates, such as succinate or lactate, has shown promising clinical outcomes in RA treatment. These findings open an avenue for the identification of novel biomarkers for diagnosis, prognosis, and determining the success of various treatments in RA patients, as well as the discovery of new therapeutic targets.
Asunto(s)
Artritis Reumatoide , Humanos , Artritis Reumatoide/tratamiento farmacológico , Membrana Sinovial/metabolismo , Inflamación/metabolismo , Pronóstico , Biomarcadores/metabolismo , Enfermedad CrónicaRESUMEN
Evidence demonstrated that metabolic-associated T cell abnormalities could be detected in the early stage of RA development. In this context, molecular evaluations have revealed changes in metabolic pathways, leading to the aggressive phenotype of RA T cells. A growing list of genes is downregulated or upregulated in RA T cells, and most of these genes with abnormal expression fall into the category of metabolic pathways. It has been shown that RA T cells shunt glucose towards the pentose phosphate pathway (PPP), which is associated with a high level of nicotinamide adenine dinucleotide phosphate (NADPH) and intermediate molecules. An increased level of NADPH inhibits ATM activation and thereby increases the proliferation capabilities of the RA T cells. Defects in the DNA repair nuclease MRE11A cause failures in repairing mitochondrial DNA, resulting in inhibiting the fatty acid oxidation pathway and further elevated cytoplasmic lipid droplets. Accumulated lipid droplets employ to generate lipid membranes for the cell building program and are also used to form the front-end membrane ruffles that are accomplices with invasive phenotypes of RA T cells. Metabolic pathway involvement in RA pathogenesis expands the pathogenic concept of the disease beyond the common view of autoimmunity triggered by autoantigen recognition. Increased knowledge about metabolic pathways' implications in RA pathogenesis paves the way to understand better the environment/gene interactions and host/microbiota interactions and introduce potential therapeutic approaches. This review summarized emerging data about the roles of T cells in RA pathogenesis with a focus on immunometabolism dysfunctions and how these metabolic alterations can affect the disease process.
Asunto(s)
Artritis Reumatoide , Linfocitos T , Humanos , Linfocitos T/metabolismo , NADP/metabolismo , Artritis Reumatoide/metabolismo , Autoinmunidad , Autoantígenos/metabolismoRESUMEN
INTRODUCTION AND OBJECTIVE: Developmental dysplasia of the hip (DDH) is a musculoskeletal disorder. Genetic and epigenetic changes in C-X3-C motif chemokine receptor 1 (CX3CR1) may lead to disturbance in chondrocyte development and change the labrum dimensions, which indirectly result in hip joint instability. Considering the important role of this gene in cell migration, cell adhesion and bone and cartilage development, we aimed to evaluate the CX3CR1 gene methylation in DDH pathogenesis. METHODS: Our study comprised of forty-five DDH patients and forty-five healthy control subjects with healthy femoral neck cartilage. The healthy controls had total or hemiarthroplasty for the femoral neck fracture. Samples were collected from the femoral head (cartilage) of DDH patients and healthy controls. Genomic DNA was obtained from the samples, and DNA methylation of CX3CR1 gene was analyzed via metabisulfite method. RESULTS: Methylation analysis reveals no significant differences in promoter of CX3CR1 gene in cartilage samples from DDH patients and healthy control subjects (P = 0.33). CONCLUSION: Methylation status of CX3CR1 gene showed no significant difference between the patient and control groups. Our results indicate that DNA methylation may not modulate this gene in this disease and other epigenetic mechanisms such as non-coding RNAs and histone modifications could be implicated.
Asunto(s)
Displasia del Desarrollo de la Cadera , Luxación Congénita de la Cadera , Receptor 1 de Quimiocinas CX3C/genética , ADN , Metilación de ADN/genética , Luxación Congénita de la Cadera/cirugía , Humanos , Receptores de Quimiocina/genéticaRESUMEN
CRS with nasal polyps (CRSwNP) is a multifactorial disease, and various etiological factors like bacterial superantigens are known to develop this disease. Recent studies reported that Staphylococcus aureus nasal colonization was detected in 67% of the patients with CRSwNP. Moreover, it was reported that specific IgE against S. aureus enterotoxins are discovered in almost half of the nasal tissue homogenates from nasal polyps. Thus, investigations have highlighted the role of staphylococcal enterotoxins, especially enterotoxin B (SEB), in pathogenesis of CRSwNP. The destruction of mucosal integrity was reported as a main SEB-related pathogenic mechanisms in CRSwNP. SEB activates Toll Like Receptor 2 and triggers the production of pro-inflammatory cytokines; furthermore, it induces reactive oxygen species and endoplasmic reticulum stress-induced inflammation that may cause epithelial cell integrity disruption and enhance their permeability. SEB-induced Type 2/Th2 pathway results in degranulation of eosinophils, cationic proteins production, and localized eosinophilic inflammation. Furthermore, SEB may be involved in the expression of RORC and HIF-1α in Tregs and by maintaining the inflammation in sinonasal mucosa that could have a main role in the pathogenesis of nasal polyposis. Different in vitro findings were confirmed in animal studies; however, in vivo analysis of SEB-induced nasal polyps and CRS remains unfulfilled due to the lack of appropriate animal models. Finally, after elucidating different aspects of SEB pathogenesis in CRSwNP, therapeutic agents have been tested in recent studies with some encouraging results. The purpose of this article is to summarize the most important findings regarding SEB-induced CRS and nasal polyposis. Video Abstract.
Asunto(s)
Pólipos Nasales , Rinitis , Sinusitis , Animales , Enfermedad Crónica , Enterotoxinas/farmacología , Humanos , Inflamación/complicaciones , Pólipos Nasales/complicaciones , Pólipos Nasales/metabolismo , Rinitis/complicaciones , Rinitis/microbiología , Sinusitis/complicaciones , Sinusitis/microbiología , Staphylococcus aureusRESUMEN
Introduction: The variety of the genetic factors playing role in development of dental caries calls for further research in this regard. The aim of the present study was to investigate the differences between caries-free adults and adults with dental caries in terms of polymorphism of caries-related genes (AMELX and ENAM). Methods: The present case-control study was performed on 81 adults aged 18-24 years, 41 caries free, and 40 with a DMFT ≥ 4. A questionnaire containing background and demographic information (such as age, gender, time and type of latest dental check-ups, parent's education, oral self-care, and the place of residence in the first 12 years of life) was completed by participants at the time of examination. The blood sample was taken from each participant in the EDTA tube, and PCR was performed. Gene diversity of AMELX and ENAM genes was compared between the two groups. Results: Regarding AMELX gene, in the caries-free group 33 (80.5%) and in the group with DMFT ≥ 4, 33 (82.5%) students had TT genotype, but this difference was insignificant. For ENAM gene, in the caries-free group 34 (82.9%) and in the group with DMFT ≥ 4, 39 (97.5%) students had TT genotype, but this difference was insignificant (P value = 0.048, CI 95%:0.02-1.27, and OR = 0.145). Conclusion: There was no relationship between TT and TC genotypes of single nucleotide polymorphism of AMELX and ENAM gene and susceptibility to dental caries, but with increasing sample size, there may be a relationship between SNP of ENAM gene and being caries free.
RESUMEN
Fibroblast-like synoviocytes (FLSs) produce lots of inflammatory molecules that trigger immune responses and intensification the inflammation and thereby play important roles in Rheumatoid Arthritis )RA( pathogenesis. Due to the important roles of toll-like receptor 4 (TLR4) in cytokine production and inflammation, we aimed to evaluate the effects of TAK-242 (Resatorvid) on interleukin (IL)1-ß, IL-6, TNF-α, and TLR4 expression and two important proteins of nuclear factor-κB (NF-κB) signaling pathway (Ikßα and pIkßα) in RA and trauma FLSs. FLSs were isolated from synovial tissues of trauma (n=10) and RA (n=10) patients and cultured in Dulbecco's Modified Eagle Medium (DMEM). 3-[4,5-dimethylthiazole-2-yl]-2,5-diphenyltetrazolium bromide (MTT) was performed to evaluate the cytotoxicity effects of TAK-242 on the RA FLSs. Real-time PCR was performed to measure the expression level of IL1-ß, IL-6, TNF-α, and TLR4 genes in Lipopolysaccharide (LPS) and TAK-242 treated FLSs. Furthermore, the treated FLSs were evaluated for protein levels of Ikßα and pIkßα by western blot. The baseline expression of IL1-ß, IL-6, TNF-α, and TLR4 showed no significant differences between healthy and RA FLSs. LPS stimulated FLSs significantly increased mRNA levels of IL-1ß, IL-6, TNF-α, and TLR4 genes in both the healthy and RA FLSs compared with that of their control groups, and pretreatment with TAK-242 reversed the effect. Furthermore, LPS-stimulated FLSs significantly increased the level of pIkßα in both the healthy and RA FLSs compared with that of their control groups, and pretreatment with TAK-242 reversed the effect. We provide the data that TAK-242 through inhibiting the NF-κB signaling pathway may modulate TLR4-mediated inflammatory responses and could be considered as a potential therapeutic agent for RA patients.
Asunto(s)
Antiinflamatorios/farmacología , Artritis Reumatoide/metabolismo , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Sulfonamidas/farmacología , Sinoviocitos/efectos de los fármacos , Sinoviocitos/metabolismo , Antiinflamatorios/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/etiología , Artritis Reumatoide/patología , Biomarcadores , Células Cultivadas , Citocinas/genética , Citocinas/metabolismo , Susceptibilidad a Enfermedades , Regulación de la Expresión Génica , Humanos , Mediadores de Inflamación/metabolismo , FN-kappa B/metabolismo , Transducción de Señal , Sulfonamidas/uso terapéutico , Sinoviocitos/patologíaRESUMEN
Fibroblast-like synoviocytes (FLSs) have been introduced in recent years as a key player in the pathogenesis of rheumatoid arthritis (RA), but the exact mechanisms of their transformation and intracellular pathways have not yet been determined. This study aimed to investigate the role of fibroblast activation protein-alpha (FAP-α) in the regulation of genes involved in the transformation and pathogenic activity of RA FLSs. Synovial FLSs were isolated from RA patients and non-arthritic individuals (n=10 in both groups) and characterized; using immunocytochemistry and flow cytometry analysis. FLSs were divided into un-treated and Talabostat-treated groups to evaluate the FAP-α effect on the selected genes involved in cell cycle regulation (p21, p53, CCND1), apoptosis (Bcl-2, PUMA), and inflammatory and destructive behavior of FLSs (IL-6, TGF-ß1, MMP-2, MMP-9, P2RX7). Gene expression analysis was performed by quantitative real-time polymerase chain reaction (qRT-PCR), and immunoblotting was carried out to evaluate FAP-α protein levels. The basal level of FAP-α protein in RA patients was significantly higher than non-arthritic control individuals. However, no differences were observed between RA and non-arthritic FLSs, at the baseline mRNA levels of all the genes. Talabostat treatment significantly reduced FAP-α protein levels in both RA and non-arthritic FLSs, however, had no effect on mRNA expressions except an upregulated TGF-ß1 expression in non-arthritic FLSs. A significantly higher protein level of FAP-α in FLSs of RA patients compared with that of healthy individuals may point to the pathogenic role of this protein in RA FLSs. However, more investigations are necessary to address the mechanisms mediating the FAP-α pathogenic role in RA FLSs.
Asunto(s)
Artritis Reumatoide/metabolismo , Endopeptidasas/metabolismo , Fibroblastos/metabolismo , Proteínas de la Membrana/metabolismo , Sinoviocitos/metabolismo , Adulto , Anciano , Proteínas Reguladoras de la Apoptosis/genética , Proteínas Reguladoras de la Apoptosis/metabolismo , Artritis Reumatoide/genética , Artritis Reumatoide/patología , Estudios de Casos y Controles , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Células Cultivadas , Femenino , Fibroblastos/patología , Regulación de la Expresión Génica , Humanos , Mediadores de Inflamación/metabolismo , Masculino , Persona de Mediana Edad , Transducción de Señal , Sinoviocitos/patologíaRESUMEN
Recent advances in cancer immunotherapy have raised hopes for treating cancers that are resistant to conventional therapies. Among the various immunotherapy methods, the immune checkpoint (IC) blockers were more promising and have paved their way to the clinic. Tumor cells induce the expression of ICs on the immune cells and derive them to a hyporesponsive exhausted phenotype. IC blockers could hinder immune exhaustion in the tumor microenvironment and reinvigorate immune cells for an efficient antitumor response. Despite the primary success of IC blockers in the clinic, the growing numbers of refractory cases require an in-depth study of the cellular and molecular mechanisms underlying IC expression and function. Immunometabolism is recently found to be a key factor in the regulation of immune responses. Activated or exhausted immune cells exploit different metabolic pathways. Tumor cells can suppress antitumor responses via immunometabolism alteration. Therefore, it is expected that concurrent targeting of ICs and immunometabolism pathways can cause immune cells to restore their antitumor activity. In this review, we dissected the reciprocal interactions of immune cell metabolism with expression and signaling of ICs in the tumor microenvironment. Recent findings on dual targeting of ICs and metabolic checkpoints have also been discussed.
Asunto(s)
Neoplasias , Antineoplásicos/uso terapéutico , Biomarcadores de Tumor/inmunología , Biomarcadores de Tumor/metabolismo , Humanos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inmunomodulación , Inmunoterapia , Neoplasias/inmunología , Neoplasias/metabolismo , Neoplasias/terapia , Microambiente TumoralRESUMEN
Swelling and the progressive destruction of articular cartilage are major characteristics of rheumatoid arthritis (RA), a systemic autoimmune disease that directly affects the synovial joints and often causes severe disability in the affected positions. Recent studies have shown that type B synoviocytes, which are also called fibroblast-like synoviocytes (FLSs), as the most commonly and chiefly resident cells, play a crucial role in early-onset and disease progression by producing various mediators. During the pathogenesis of RA, the FLSs' phenotype is altered, and represent invasive behavior similar to that observed in tumor conditions. Modified and stressful microenvironment by FLSs leads to the recruitment of other immune cells and, eventually, pannus formation. The origins of this cancerous phenotype stem fundamentally from the significant metabolic changes in glucose, lipids, and oxygen metabolism pathways. Moreover, the genetic abnormalities and epigenetic alterations have recently been implicated in cancer-like behaviors of RA FLSs. In this review, we will focus on the mechanisms underlying the transformation of FLSs to a cancer-like phenotype during RA. A comprehensive understanding of these mechanisms may lead to devising more effective and targeted treatment strategies.
RESUMEN
Fibroblast-like synoviocytes (FLSs) are important non-immune cells located mostly in the inner layer of the synovium. Indeed, these cells are specialized mesenchymal cells, implicated in collagen homeostasis of the articular joint and provide extracellular matrix (ECM) materials for cartilage and contribute to joint destruction via multiple mechanisms. RA FLS interactions with immune and non-immune cells lead to the development and organization of tertiary structures such as ectopic lymphoid-like structures (ELSs), tertiary lymphoid organs (TLOs), and secretion of proinflammatory cytokines. The interaction of RA FLS cells with immune and non-immune cells leads to stimulation and activation of effector immune cells. Pathological role of RA FLS cells has been reported for many years, while molecular and cellular mechanisms are not completely understood yet. In this review, we tried to summarize the latest findings about the role of FLS cells in ELS formation, joint destruction, interactions with immune and non-immune cells, as well as potential therapeutic options in rheumatoid arthritis (RA) treatment. Our study revealed data about interactions between RA FLS and immune/non-immune cells as well as the role of RA FLS cells in joint damage, ELS formation, and neoangiogenesis, which provide useful information for developing new approaches for RA treatment.
Asunto(s)
Artritis Reumatoide/patología , Fibroblastos/patología , Articulaciones/patología , Sinoviocitos/patología , Estructuras Linfoides Terciarias/patología , Artritis Reumatoide/inmunología , Artritis Reumatoide/metabolismo , Citocinas/inmunología , Citocinas/metabolismo , Fibroblastos/inmunología , Fibroblastos/metabolismo , Humanos , Articulaciones/inmunología , Articulaciones/metabolismo , Sinoviocitos/inmunología , Sinoviocitos/metabolismo , Estructuras Linfoides Terciarias/inmunología , Estructuras Linfoides Terciarias/metabolismoRESUMEN
Several studies have evaluated the association between killer-cell immunoglobulin-like receptors (KIR) genes and susceptibility risk to tuberculosis (TB) infection. Nonetheless, their outcomes have not been conclusive and consistent. Here we implemented a systematic review and meta-analysis of KIR genes association to susceptibility risk of pulmonary TB (PTB) infection to attain a clear understanding of the involvement of these genes in susceptibility to PTB infection. A systematic search was conducted in the MEDLINE/PubMed and Scopus databases to find case-control studies published before November 2020. Pooled odds ratio (OR) and 95% confidence interval (95% CI) were calculated to determine the association between KIR genes and risk of PTB infection. After comprehensive searching and implementing the inclusion and exclusion criteria, 10 case-control studies were included in the meta-analysis. Four KIR genes were found to have significant positive association with PTB susceptibility risk of infection, including 2DL3 (OR = 1.454, 95% CI = 1.157-1.827; P = 0.001), 2DS1 (OR = 1.481, 95% CI = 1.334-1.837; P < 0.001), 2DS4 (OR = 1.782, 95% CI = 1.273-2.495; P = 0.001) and 3DL1 (OR = 1.726, 95% CI = 1.277-2.333; P < 0.001). However, the results showed that the remaining KIR genes (2DS2-4, 2DL1, 2, 4, 3DL1-2) and two pseudogenes (2DP1 and 3DP1) did not have significant associations with risk of PTB infection. This meta-analysis provides reliable evidence that the KIR genes 2DL3, 2DS1, 2DS4, and 3DL1 may be associated with an increased risk of PTB infection.
Asunto(s)
Receptores KIR , Tuberculosis Pulmonar , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Receptores KIR/genética , Tuberculosis Pulmonar/genéticaRESUMEN
Glucose metabolism is considerably increased in inflamed joints of rheumatoid arthritis (RA) patients at early stages. Fibroblast-like synoviocytes (FLSs) activation and subsequent joint damage are linked with metabolic alterations, especially glucose metabolism. It has been shown that glucose metabolism is elevated in aggressive phenotype of FLS cells. In this regard, glycolytic blockers are able to reduce aggressiveness of the FLS cells resulting in decreased joint damage in various arthritis models. Besides, metabolic changes in immune and non-immune cells such as FLS can provide important targets for therapeutic intervention. Glycolytic enzymes such as hexokinase 2 (HK2), phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB), and phosphoglycerate kinase (PGK) play essential roles in aggressive behavior of FLS cells. It has been documented that the HK2 enzyme is significantly upregulated in RA FLS cells, compared with osteoarthritis (OA) FLS cells. The HK2 is expressed in a few tissues and upregulated in the inflamed synovium of RA patients that makes it a potential target for RA treatment. Furthermore, HK2 has different roles in each cellular compartment, which offers another level of specificity and provides a specific target to reduce deleterious effects of inhibiting the enzyme in RA without affecting glycolysis in normal cells. Thus, targeting the HK2 enzyme might be an attractive potential selective target for arthritis therapy and safer than global glycolysis inhibition. Therefore, this review was aimed to summarize the current knowledge about glucose metabolism of FLS cells and suggest novel biomarkers, which are potential candidates for RA treatment.
Asunto(s)
Antiinflamatorios/farmacología , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/metabolismo , Glucosa/metabolismo , Sinoviocitos/efectos de los fármacos , Sinoviocitos/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , HumanosRESUMEN
Genetic studies have illustrated that killer cell immunoglobulin-like receptor (KIR) genes could participate in various autoimmune disorders. We aimed to clarify the role of KIR genes, HLA ligands, HLA-KIR interactions, and their genotypes in inflammatory bowel disease (IBD) susceptibility. The study population was composed of 183 IBD subjects, comprising 100 ulcerative colitis (UC) patients, 83 Crohn's disease (CD) patients, and 274 healthy subjects. Polymerase chain reaction with sequence-specific primers (PCR-SSP) was used to evaluate the absence or presence of the 15 KIR genes, 5 HLA class I ligands, and 2 pseudogenes. We did not find any significant difference in allele frequency of KIRs and pseudogenes between IBD patients and healthy controls. In the case of HLA genes, there was a significant difference in HLA-B-Bw4Thr80 frequency between UC patients and healthy controls (P = 0.03, OR = 0.06, 95%CI = 0.008-0.4). Furthermore, we found a significant difference in HLA-C1Asn80 frequency between CD patients and healthy controls (P = 0.04, OR = 0.49, 95% CI = 0.3-0.8). In the full-array combination of KIR genes, there was no significant frequency difference between UC patients and healthy controls, while two KIR genotypes showed a significant susceptible association with CD. Our data do not support a strong role of NK cells in IBD susceptibility, but it does not rule out a role for KIR variability in IBD patients. However, there are some protective associations such as Bw4 alleles; these associations may be due to the interaction of the alleles to TCRs rather than KIRs.