Control of T(H)17/T(reg) balance by hypoxia-inducible factor 1.

T cell differentiation into distinct functional effector and inhibitory subsets is regulated, in part, by the cytokine environment present at the time of antigen recognition. Here, we show that hypoxia-inducible factor 1 (HIF-1), a key metabolic sensor, regulates the balance between regulatory T cell (T(reg)) and T(H)17 differentiation. HIF-1 enhances T(H)17 development through direct transcriptional activation of RORγt and via tertiary complex formation with RORγt and p300 recruitment to the IL-17 promoter, thereby regulating T(H)17 signature genes. Concurrently, HIF-1 attenuates T(reg) development by binding Foxp3 and targeting it for proteasomal degradation. Importantly, this regulation occurs under both normoxic and hypoxic conditions. Mice with HIF-1α-deficient T cells are resistant to induction of T(H)17-dependent experimental autoimmune encephalitis associated with diminished T(H)17 and increased T(reg) cells. These findings highlight the importance of metabolic cues in T cell fate determination and suggest that metabolic modulation could ameliorate certain T cell-based immune pathologies.

MicroRNA-17 Modulates Regulatory T Cell Function by Targeting Co-regulators of the Foxp3 Transcription Factor.

Regulatory T (Treg) cells are important in maintaining self-tolerance and immune homeostasis. The Treg cell transcription factor Foxp3 works in concert with other co-regulatory molecules, including Eos, to determine the transcriptional signature and characteristic suppressive phenotype of Treg cells. Here, we report that the inflammatory cytokine interleukin-6 (IL-6) actively repressed Eos expression through microRNA-17 (miR-17). miR-17 expression increased in Treg cells in the presence of IL-6, and its expression negatively correlated with that of Eos. Treg cell suppressive activity was diminished upon overexpression of miR-17 in vitro and in vivo, which was mitigated upon co-expression of an Eos mutant lacking miR-17 target sites. Also, RNAi of miR-17 resulted in enhanced suppressive activity. Ectopic expression of miR-17 imparted effector-T-cell-like characteristics to Treg cells via the de-repression of genes encoding effector cytokines. Thus, miR-17 provides a potent layer of Treg cell control through targeting Eos and additional Foxp3 co-regulators.

Exploring nontraditional cardiorenal advantages of SGLT-2 inhibitors and GLP-1 receptor agonists.

This commentary provides an analysis of the study by Fu et al. in Kidney International, which employs 3 administrative databases to investigate the hyperkalemia protective effects of sodium-glucose cotransporter-2 inhibitors, glucagon-like peptide-1 receptor agonists, and dipeptidyl peptidase-4 inhibitors. It emphasizes the methodological approach, notably the use of a fixed-effect model to aggregate pairwise comparisons from 3 data sets. In addition, we explored the broader cardiorenal and potential nonrenal benefits of these drug classes, underscoring the imperative for continued research in this domain.

Metformin induces lactate accumulation and accelerates renal cyst progression in Pkd1-deficient mice.

Metabolic reprogramming is a potential treatment strategy for autosomal dominant polycystic kidney disease (ADPKD). Metformin has been shown to inhibit the early stages of cyst formation in animal models. However, metformin can lead to lactic acidosis in diabetic patients with advanced chronic kidney disease, and its efficacy in ADPKD is still not fully understood. Here, we investigated the effect of metformin in an established hypomorphic mouse model of PKD that presents stable and heritable knockdown of Pkd1. The Pkd1 miRNA transgenic mice of both genders were randomized to receive metformin or saline injections. Metformin was administrated through daily intraperitoneal injection from postnatal day 35 for 4 weeks. Unexpectedly, metformin treatment at a concentration of 150 mg/kg increased disease severity, including kidney-to-body weight ratio, cystic index and plasma BUN levels, and was associated with increased renal tubular cell proliferation and plasma lactate levels. Functional enrichment analysis for cDNA microarrays from kidney samples revealed significant enrichment of several pro-proliferative pathways including ß-catenin, hypoxia-inducible factor-1α, protein kinase Cα and Notch signaling pathways in the metformin-treated mutant mice. The plasma metformin concentrations were still within the recommended therapeutic range for type 2 diabetic patients. Short-term metformin treatment in a second Pkd1 hypomorphic model (Pkd1RC/RC) was however neutral. These results demonstrate that metformin may exacerbate late-stage cyst growth associated with the activation of lactate-related signaling pathways in Pkd1 deficiency. Our findings indicate that using metformin in the later stage of ADPKD might accelerate disease progression and call for the cautious use of metformin in these patients.

Gut flora metagenomic analysis coupled with metabolic and deep immune profiling in chronic kidney disease.

BACKGROUND AND HYPOTHESIS: Perturbation of gut microbiota has been linked to chronic kidney disease (CKD), which was correlated with a sophisticated milieu of metabolic and immune dysregulation. METHODS: To clarify the underlying host-microbe interaction in CKD, we performed multi-omics measurements, including systems-level gut microbiome, targeted serum metabolome, and deep immunotyping, in a cohort of patients and non-CKD controls. RESULTS: Our analyses on functional profiles of gut microbiome showed a decrease in the diversity and abundance of carbohydrate-active enzyme (CAZyme) genes but an increase in the abundance of antibiotic resistance, nitrogen cycling enzyme, and virulence factor genes in CKD. Moreover, models generated using measurements of serum metabolites (amino acids, bile acids, and short-chain fatty acids) or immunotypes were predictive of renal impairment but less so than many of functional profiles derived from gut microbiota, with the CAZyme genes being the top performing model to accurately predict early stage of diseases. In addition, co-occurrence analyses revealed coordinated host-microbe relationships in CKD. Specifically, the highest fractions of significant correlations were identified with circulating metabolites by several taxonomic and functional profiles of gut microbiome, while immunotype features were moderately associated with the abundance of microbiome-encoded metabolic pathways and serum levels of amino acids (e.g. B cell cluster-tryptophan and B cell cluster-tryptophan metabolism). CONCLUSION: Overall, our multi-omics integration revealed several signatures of systems-level gut microbiome in robust associations with host-microbe co-metabolites and renal function, which may be of etiological and diagnostic implications in CKD.

Transcriptome landscape reveals the chronic inflammatory response in kidneys affected by the combinatory effect of leptospirosis and nephrotoxic injury.

Leptospirosis can cause chronic kidney damage, putting patients at risk of additional kidney injury due to other factors that can lead to renal failure. To understand the combined effect, the transcriptome profiles of kidneys of mice with adenine-induced and chronically Leptospira-infected kidneys were analysed. Chronic inflammation and T-helper 17 immune responses were activated and a high-level expression of Indoleamine 2,3-dioxygenase 1 protein was found. The results indicate that the combination may predispose patients to chronic inflammation, kidney function disruption, and symptoms seen in progressive chronic kidney disease (CKD). Furthermore, immunometabolic regulation may contribute to renal injury caused by chronic leptospirosis with secondary nephrotoxic injury. This study identified several significantly disrupted genes that could serve as potential targets for the diagnosis or treatment of CKD. Our work provides insight into the combined effect of leptospirosis and secondary kidney damage and the molecular basis for rapid progression of CKD.

Contribution of genetic variants associated with primary immunodeficiencies to childhood-onset systemic lupus erythematous.

BACKGROUND: A dysregulated immune response is a hallmark of autoimmune disorders. Evidence suggests that systemic autoimmune diseases and primary immunodeficiency disorders (PIDs) may be similar diseases with different clinical phenotypes. OBJECTIVE: This study aimed to investigate the burden of PID-associated genetic variants in patients with childhood-onset systemic lupus erythematosus (cSLE). METHODS: We enrolled 118 cSLE patients regularly followed at Chang Gung Memorial Hospital. Targeted next-generation sequencing identified PID genetic variants in patients versus 1475 unrelated healthy individuals, which were further filtered by allelic frequency and various functional scores. Customized immune assays tested the functions of the identified variants. RESULTS: On filtration, 36 patients (30.5%) harbored rare variants in PID-associated genes predicted to be damaging. One homozygous TREX1 (c.294dupA) mutation and 4 heterozygous variants with possible dominant PID traits, including BCL11B (c.G1040T), NFKB1 (c.T695G), and NFKB2 (c.G1210A, c.G1651A), were discovered. With recessive traits, variants were found across all PID types; one fifth involved phagocyte number or function defects. Predicted pathogenic PID variants were more predominant in those with a family history of lupus, regardless of infection susceptibility. Moreover, mutation loads were greater among cSLE patients than controls despite sex or age at disease onset. While greater mutation loads were observed among cSLE patients with peripubertal disease onset, no significant differences in sex or phenotype were noted among cSLE patients. CONCLUSION: cSLE is mostly not monogenic. Gene-specific analysis and mutation load investigations suggested that rare and predicted damaging variants in PID-related genes can potentially contribute to cSLE susceptibility.

Tumor necrosis factor-alpha blockade suppresses BK polyomavirus replication.

PURPOSE: BK Polyomavirus (BKPyV) infection manifests as renal inflammation and can cause kidney damage. Tumor necrosis factor-α (TNF-α) is increased in renal inflammation and injury. The aim of this study was to investigate the effect of TNF-α blockade on BKPyV infection. METHODS: Urine specimens from 22 patients with BKPyV-associated nephropathy (BKPyVN) and 35 non-BKPyVN kidney transplant recipients were analyzed. RESULTS: We demonstrated increased urinary levels of TNF-α and its receptors, TNFR1 and TNFR2, in BKPyVN patients. Treating BKPyV-infected human proximal tubular cells (HRPTECs) with TNF-α stimulated the expression of large T antigen and viral capsid protein-1 mRNA and proteins and BKPyV promoter activity. Knockdown of TNFR1 or TNFR2 expression caused a reduction in TNF-α-stimulated viral replication. NF-κB activation induced by overexpression of constitutively active IKK2 significantly increased viral replication and the activity of the BKPyV promoter containing an NF-κB binding site. The addition of a NF-κB inhibitor on BKPyV-infected cells suppressed viral replication. Blockade of TNF-α functionality by etanercept reduced BKPyV-stimulated expression of TNF-α, interleukin-1ß (IL-1ß), IL-6 and IL-8 and suppressed TNF-α-stimulated viral replication. In cultured HRPTECs and THP-1 cells, BKPyV infection led to increased expression of TNF-α, interleukin-1 ß (IL-1ß), IL-6 and TNFR1 and TNFR2 but the stimulated magnitude was far less than that induced by poly(I:C). This may suggest that BKPyV-mediated autocrine effect is not a major source of TNFα. CONCLUSION: TNF-α stimulates BKPyV replication and inhibition of its signal cascade or functionality attenuates its stimulatory effect. Our study provides a therapeutic anti-BKPyV target.

The ubiquitin ligase Stub1 negatively modulates regulatory T cell suppressive activity by promoting degradation of the transcription factor Foxp3.

Regulatory T (Treg) cells suppress inflammatory immune responses and autoimmunity caused by self-reactive T cells. The key Treg cell transcription factor Foxp3 is downregulated during inflammation to allow for the acquisition of effector T cell-like functions. Here, we demonstrate that stress signals elicited by proinflammatory cytokines and lipopolysaccharides lead to the degradation of Foxp3 through the action of the E3 ubiquitin ligase Stub1. Stub1 interacted with Foxp3 to promote its K48-linked polyubiquitination in an Hsp70-dependent manner. Knockdown of endogenous Stub1 or Hsp70 prevented Foxp3 degradation. Furthermore, the overexpression of Stub1 in Treg cells abrogated their ability to suppress inflammatory immune responses in vitro and in vivo and conferred a T-helper-1-cell-like phenotype. Our results demonstrate the critical role of the stress-activated Stub1-Hsp70 complex in promoting Treg cell inactivation, thus providing a potential therapeutic target for the intervention against autoimmune disease, infection, and cancer.

Pharmacological and non-pharmacological treatments for restless legs syndrome in end-stage kidney disease: a systematic review and component network meta-analysis.

BACKGROUND: Restless legs syndrome (RLS) is common among patients with end-stage kidney disease (ESKD) and is associated with poor outcomes. Several recently published studies had focused on pharmacological and non-pharmacological treatments of RLS, but an updated meta-analysis has not been conducted. METHODS: The study population was adult ESKD patients on dialysis with RLS. Randomized controlled trials (RCTs) were selected. The primary outcome was reduction in RLS severity. The secondary outcomes were improvement in sleep quality and treatment-related adverse events. Frequentist standard network meta-analysis (NMA) and additive component NMA were performed. The evidence certainty was assessed using the Confidence in NMA (CINeMA) framework. RESULTS: A total of 24 RCTs with 1252 participants were enrolled and 14 interventions were compared. Cool dialysate produced the largest RLS severity score reduction {mean difference [MD] 16.82 [95% confidence interval (CI) 10.635-23.02]} and a high level of confidence. Other potential non-pharmacological interventions include intradialytic stretching exercise [MD 12.00 (95% CI 7.04-16.97)] and aromatherapy massage [MD 10.91 (95% CI 6.96-14.85)], but all with limited confidence of evidence. Among the pharmacological interventions, gabapentin was the most effective [MD 8.95 (95% CI 1.95-15.85)], which also improved sleep quality [standardized MD 2.00 (95% CI 0.47-3.53)]. No statically significant adverse events were detected. CONCLUSIONS: The NMA supports that cool dialysate is appropriate to treat patients with ESKD and RLS. Gabapentin is the most effective pharmacological intervention and also might improve sleep quality. Further parallel RCTs with sufficient sample sizes are required to evaluate these potential interventions and long-term effects.

Transcriptomic signatures of exacerbated progression in leptospirosis subclinical chronic kidney disease with secondary nephrotoxic injury.

High-incidence regions of leptospirosis caused by Leptospira spp. coincide with chronic kidney disease. This study investigated whether asymptomatic leptospirosis is an emerging culprit that predisposes to progressive chronic kidney disease when superimposed on secondary nephrotoxic injury. Kidney histology/function and whole transcriptomic profiles were evaluated for Leptospira-infected C57/BL6 mice with adenine-induced kidney injury. The extent of tubulointerstitial kidney lesions and expression of inflammation/fibrosis genes in infected mice with low-dose (0.1%) adenine, particularly in high-dose (0.2%) adenine-fed superimposed on Leptospira-infected mice, were significantly increased compared with mice following infection or adenine diet alone, and the findings are consistent with renal transcriptome analysis. Pathway enrichment findings showed that integrin-ß- and fibronectin-encoding genes had distinct expression within the integrin-linked kinase-signaling pathway, which were upregulated in 0.2% adenine-fed Leptospira-infected mice but not in 0.2% adenine-fed mice, indicating that background subclinical Leptospiral infection indeed enhanced subsequent secondary nephrotoxic kidney injury and potential pathogenic molecules associated with secondary nephrotoxic leptospirosis. Comparative analysis of gene expression patterns with unilateral ureteric obstruction-induced mouse renal fibrosis and patients with chronic kidney disease showed that differentially expressed orthologous genes such as hemoglobin-α2, PDZ-binding kinase, and DNA topoisomerase II-α were identified in infected mice fed with low-dose and high-dose adenine, respectively, revealing differentially expressed signatures identical to those found in the datasets and may serve as markers of aggravated kidney progression. This study indicates that background subclinical leptospirosis, when subjected to various degrees of subsequent secondary nephrotoxic injury, may predispose to exacerbated fibrosis, mimicking the pathophysiological process of progressive chronic kidney disease.NEW & NOTEWORTHYLeptospira-infected mice followed by secondary nephrotoxic injury exacerbated immune/inflammatory responses and renal fibrosis. Comparison with the murine model revealed candidates involved in the progression of renal fibrosis in chronic kidney disease (CKD). Comparative transcriptome study suggests that secondary nephrotoxic injury in Leptospira-infected mice recapitulates the gene expression signatures found in CKD patients. This study indicates that secondary nephrotoxic injury may exacerbate CKD in chronic Leptospira infection implicating in the progression of CKD of unknown etiology.

Signals and Mechanisms Regulating Monocyte and Macrophage Activation in the Pathogenesis of Juvenile Idiopathic Arthritis.

Monocytes (Mos) and macrophages (Mφs) are key players in the innate immune system and are critical in coordinating the initiation, expansion, and regression of many autoimmune diseases. In addition, they display immunoregulatory effects that impact inflammation and are essential in tissue repair and regeneration. Juvenile idiopathic arthritis (JIA) is an umbrella term describing inflammatory joint diseases in children. Accumulated evidence suggests a link between Mo and Mφ activation and JIA pathogenesis. Accordingly, topics regarding the signals and mechanisms regulating Mo and Mφ activation leading to pathologies in patients with JIA are of great interest. In this review, we critically summarize recent advances in the understanding of how Mo and Mφ activation is involved in JIA pathogenesis and focus on the signaling pathways and mechanisms participating in the related cell activation processes.

From Rheumatoid Factor to Anti-Citrullinated Protein Antibodies and Anti-Carbamylated Protein Antibodies for Diagnosis and Prognosis Prediction in Patients with Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease mainly involving synovial inflammation and articular bone destruction. RA is a heterogeneous disease with diverse clinical presentations, prognoses and therapeutic responses. Following the first discovery of rheumatoid factors (RFs) 80 years ago, the identification of both anti-citrullinated protein antibodies (ACPAs) and anti-carbamylated protein antibodies (anti-CarP Abs) has greatly facilitated approaches toward RA, especially in the fields of early diagnosis and prognosis prediction of the disease. Although these antibodies share many common features and can function synergistically to promote disease progression, they differ mechanistically and have unique clinical relevance. Specifically, these three RA associating auto-antibodies (autoAbs) all precede the development of RA by years. However, while the current evidence suggests a synergic effect of RF and ACPA in predicting the development of RA and an erosive phenotype, controversies exist regarding the additive value of anti-CarP Abs. In the present review, we critically summarize the characteristics of these autoantibodies and focus on their distinct clinical applications in the early identification, clinical manifestations and prognosis prediction of RA. With the advancement of treatment options in the era of biologics, we also discuss the relevance of these autoantibodies in association with RA patient response to therapy.

TAFRO Syndrome with Renal Thrombotic Microangiopathy: Insights into the Molecular Mechanism and Treatment Opportunities.

TAFRO syndrome is an extremely rare form of idiopathic MCD, characterized by thrombocytopenia, anasarca, fever, reticulin fibrosis on bone marrow biopsy, and organomegaly. Like idiopathic MCD, renal involvement is also a common presentation in patients with TAFRO syndrome. Furthermore, membranoproliferative glomerulonephritis (MPGN)-like injury and thrombotic microangiopathy (TMA) are the most reported histopathologic findings of renal biopsy. Several molecular mechanisms have been previously postulated in order to explain the TAFRO syndrome symptoms, including abnormal production of interleukin-6 (IL-6), vascular endothelial growth factor (VEGF), etc. The role of these cytokines in renal injury, however, is not well understood. The aim of this review article is to summarize the latest knowledge of molecular mechanisms behind the TAFRO syndrome and their potential role in renal damage.

Crosstalk between E-Cadherin/ß-Catenin and NF-κB Signaling Pathways: The Regulation of Host-Pathogen Interaction during Leptospirosis.

Approximately 1 million cases of leptospirosis, an emerging infectious zoonotic disease, are reported each year. Pathogenic Leptospira species express leucine-rich repeat (LRR) proteins that are rarely expressed in non-pathogenic Leptospira species. The LRR domain-containing protein family is vital for the virulence of pathogenic Leptospira species. In this study, the biological mechanisms of an essential LRR domain protein from pathogenic Leptospira were examined. The effects of Leptospira and recombinant LRR20 (rLRR20) on the expression levels of factors involved in signal transduction were examined using microarray, quantitative real-time polymerase chain reaction, and western blotting. The secreted biomarkers were measured using an enzyme-linked immunosorbent assay. rLRR20 colocalized with E-cadherin on the cell surface and activated the downstream transcription factor ß-catenin, which subsequently promoted the expression of MMP7, a kidney injury biomarker. Additionally, MMP7 inhibitors were used to demonstrate that the secreted MMP7 degrades surface E-cadherin. This feedback inhibition mechanism downregulated surface E-cadherin expression and inhibited the colonization of Leptospira. The degradation of surface E-cadherin activated the NF-κB signal transduction pathway. Leptospirosis-associated acute kidney injury is associated with the secretion of NGAL, a downstream upregulated biomarker of the NF-κB signal transduction pathway. A working model was proposed to illustrate the crosstalk between E-cadherin/ß-catenin and NF-κB signal transduction pathways during Leptospira infection. Thus, rLRR20 of Leptospira induces kidney injury in host cells and inhibits the adhesion and invasion of Leptospira through the upregulation of MMP7 and NGAL.

Ets1 Promotes the Differentiation of Post-Selected iNKT Cells through Regulation of the Expression of Vα14Jα18 T Cell Receptor and PLZF.

The transcription factor Ets1 is essential for the development/differentiation of invariant Natural Killer T (iNKT) cells at multiple stages. However, its mechanisms of action and target genes in iNKT cells are still elusive. Here, we show that Ets1 is required for the optimal expression of the Vα14Jα18 T cell receptor (TCR) in post-selected thymic iNKT cells and their immediate differentiation. Ets1 is also critical for maintaining the peripheral homeostasis of iNKT cells, which is a role independent of the expression of the Vα14Jα18 TCR. Genome-wide transcriptomic analyses of post-selected iNKT cells further reveal that Ets1 controls leukocytes activation, proliferation differentiation, and leukocyte-mediated immunity. In addition, Ets1 regulates the expression of ICOS and PLZF in iNKT cells. More importantly, restoring the expression of PLZF and the Vα14Jα18 TCR partially rescues the differentiation of iNKT cells in the absence of Ets1. Taken together, our results establish a detailed molecular picture of how Ets1 regulates the stepwise differentiation of iNKT cells.

AhR-ROR-γt complex is a therapeutic target for MAP4K3/GLKhighIL-17Ahigh subpopulation of systemic lupus erythematosus.

The cytokine IL-17A plays critical roles in the pathogenesis of autoimmune diseases. The frequencies of MAP kinase kinase kinase kinase 3 [also named germinal center kinase-like kinase (GLK)]-overexpressing T cells are correlated with disease severity of systemic lupus erythematosus (SLE). T-cell-specific GLK-transgenic mice develop spontaneous autoimmune responses through IL-17A. GLK signaling selectively stimulates IL-17A production in murine T cells through inducing aryl hydrocarbon receptor (AhR)-retinoic acid receptor-related orphan nuclear receptor-γt (ROR-γt) complex formation. Here, we investigated whether GLK-induced AhR-ROR-γt complex in T cells is a therapeutic target for human SLE. The population of GLK+IL-17A+ T cells was enhanced in the peripheral blood from patients with SLE compared with that of healthy controls using flow cytometry. The receiver operating characteristic curve analysis showed that increased GLK+IL-17A+ T-cell population in peripheral blood reflected an active stage of SLE. In addition, peripheral blood T cells from patients with SLE displayed induction of ROR-γt phosphorylation and the AhR-ROR-γt (and AhR-phosphorylated ROR-γt) complex. Moreover, we identified a small-molecule inhibitor, verteporfin, that inhibited GLK kinase activity and AhR-ROR-γt interaction. The small-molecule inhibitor verteporfin suppressed the disease severity in autoimmune mouse models and IL-17A production in T cells from patients with SLE. Collectively, the GLK-induced AhR-ROR-γt (and AhR-phosphorylated ROR-γt) complex is a therapeutic target for the GLKhighIL-17Ahigh subpopulation of human patients with SLE.-Chuang, H.-C., Chen, Y.-M., Chen, M.-H., Hung, W.-T., Yang, H.-Y., Tseng, Y.-H., Tan, T.-H. AhR-ROR-γt complex is a therapeutic target for MAP4K3/GLKhighIL-17Ahigh subpopulation of systemic lupus erythematosus.

Treatment Strategies and Metabolic Pathway Regulation in Urothelial Cell Carcinoma: A Comprehensive Review.

For a long time, cisplatin-based chemotherapy had been viewed as first-line chemotherapy for advanced and metastatic urothelial carcinoma (UC). However, many patients with UC had been classified as cisplatin-ineligible who can only receive alternative chemotherapy with poor treatment response, and the vast majority of the cisplatin-eligible patients eventually progressed, even those with objective response with cisplatin-based chemotherapy initially. By understanding tumor immunology in UC, immune checkpoint inhibitors, targeting on programmed death 1 (PD-1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) pathways, had been proven as first-line treatment for cisplatin-ineligible metastatic UC and as second-line treatment for patients with platinum-refractory metastatic UC by the U.S Food and Drug Administration (FDA). In 2020, JAVEIN bladder 100 further reported that PD-L1 inhibitors showed benefits on prolonged survival and progression-free survival as maintenance therapy. Besides targeting on immune checkpoint, manipulation of the tumor microenvironment by metabolic pathways intervention, including inhibition on tumor glycolysis, lactate accumulation and exogenous glutamine uptake, had been investigated in the past few years. In this comprehensive review, we start by introducing traditional chemotherapy of UC, and then we summarize current evidences supporting the use of immune checkpoint inhibitors and highlight ongoing clinical trials. Lastly, we reviewed the tumor metabolic characteristic and the anti-tumor treatments targeting on metabolic pathways.

Anti-Citrullinated Protein Antibodies in Patients with Rheumatoid Arthritis: Biological Effects and Mechanisms of Immunopathogenesis.

Individuals with high anti-citrullinated protein antibody (ACPA) titers have an increased risk of developing rheumatoid arthritis (RA). Although our knowledge of the generation and production of ACPAs has continuously advanced during the past decade, our understanding on the pathogenic mechanisms of how ACPAs interact with immune cells to trigger articular inflammation is relatively limited. Citrullination disorders drive the generation and maintenance of ACPAs, with profound clinical significance in patients with RA. The loss of tolerance to citrullinated proteins, however, is essential for ACPAs to exert their pathogenicity. N-linked glycosylation, cross-reactivity and the structural interactions of ACPAs with their citrullinated antigens further direct their biological functions. Although questions remain in the pathogenicity of ACPAs acting as agonists for a receptor-mediated response, immune complex (IC) formation, complement system activation, crystallizable fragment gamma receptor (FcγR) activation, cross-reactivity to joint cartilage and neutrophil extracellular trap (NET)-related mechanisms have all been suggested recently. This paper presents a critical review of the characteristics and possible biological effects and mechanisms of the immunopathogenesis of ACPAs in patients with RA.

Manipulation of Metabolic Pathways and Its Consequences for Anti-Tumor Immunity: A Clinical Perspective.

In the relatively short history of anti-tumor treatment, numerous medications have been developed against a variety of targets. Intriguingly, although many anti-tumor strategies have failed in their clinical trials, metformin, an anti-diabetic medication, demonstrated anti-tumor effects in observational studies and even showed its synergistic potential with immune checkpoint inhibitors (ICIs) in subsequent clinical studies. Looking back from bedside-to-bench, it may not be surprising that the anti-tumor effect of metformin derives largely from its ability to rewire aberrant metabolic pathways within the tumor microenvironment. As one of the most promising breakthroughs in oncology, ICIs were also found to exert their immune-stimulatory effects at least partly via rewiring metabolic pathways. These findings underscore the importance of correcting metabolic pathways to achieve sufficient anti-tumor immunity. Herein, we start by introducing the tumor microenvironment, and then we review the implications of metabolic syndrome and treatments for targeting metabolic pathways in anti-tumor therapies. We further summarize the close associations of certain aberrant metabolic pathways with impaired anti-tumor immunity and introduce the therapeutic effects of targeting these routes. Lastly, we go through the metabolic effects of ICIs and conclude an overall direction to manipulate metabolic pathways in favor of anti-tumor responses.