TL1A inhibition for inflammatory bowel disease treatment: From inflammation to fibrosis.

The pivotal role of TL1A in modulating immune pathways crucial for inflammatory bowel disease (IBD) and intestinal fibrosis offers a promising therapeutic target. Phase 2 trials (TUSCANY and ARTEMIS-UC) evaluating an anti-TL1A antibody show progress in expanding IBD therapeutic options. First-in-human data reveal reduced expression of genes associated with extracellular matrix remodeling and fibrosis post-anti-TL1A treatment. Investigational drug TEV-48574, potentially exerting dual antifibrotic and anti-inflammatory effects, is undergoing a phase 2 basket study in both ulcerative colitis (UC) and Crohn disease (CD). Results are eagerly awaited, marking advancements in IBD therapeutics. This critical review comprehensively examines the existing literature, illuminating TL1A and the intricate role of DR3 in IBD, emphasizing the evolving therapeutic landscape and ongoing clinical trials, with potential implications for more effective IBD management.

TNFSF15 inhibits progression of diabetic retinopathy by blocking pyroptosis via interacting with GSDME.

Diabetic retinopathy is a common microvascular complication of diabetes and a leading cause of blindness. Pyroptosis has emerged as a mechanism of cell death involved in diabetic retinopathy pathology. This study explored the role of GSDME-mediated pyroptosis and its regulation by TNFSF15 in diabetic retinopathy. We found GSDME was upregulated in the progression of diabetic retinopathy. High glucose promoted GSDME-induced pyroptosis in retinal endothelial cells and retinal pigment epithelial cells, attributed to the activation of caspase-3 which cleaves GSDME to generate the pyroptosis-executing N-terminal fragment. TNFSF15 was identified as a binding partner and inhibitor of GSDME-mediated pyroptosis. TNFSF15 expression was increased by high glucose but suppressed by the caspase-3 activator Raptinal. Moreover, TNFSF15 protein inhibited high glucose- and Raptinal-induced pyroptosis by interacting with GSDME in retinal cells. Collectively, our results demonstrate TNFSF15 inhibits diabetic retinopathy progression by blocking GSDME-dependent pyroptosis of retinal cells, suggesting the TNFSF15-GSDME interaction as a promising therapeutic target for diabetic retinopathy.

Tumor necrosis factor-like cytokine 1A plays a role in inflammatory bowel disease pathogenesis.

The binding of tumor necrosis factor-like cytokine 1A (TL1A) to death receptor 3 (DR3) plays an important role in the interaction between dendritic cells (DCs) and T cells and contributes to intestinal inflammation development. However, the mechanism by which DCs expressing TL1A mediate helper T (Th) cell differentiation in the intestinal lamina propria (LP) during the pathogenesis of inflammatory bowel disease remains unclear. In this study, we found that TL1A/DR3 promoted Th1 and Th17 cell differentiation in T-T and DC-T cell interaction-dependent manners. TL1A-deficient CD4+ T cells failed to polarize into Th1/Th17 cells and did not cause colonic inflammation in a T cell transfer colitis model. Notably, TL1A was located in the cytoplasm and nuclei of DCs, positively regulated the DC-specific ICAM-grabbing nonintegrin/RAF1/nuclear factor κB signaling pathway, enhanced the antigen uptake ability of DCs, and promoted TLR4-mediated DC activation, inducing naive CD4+ T cell differentiation into Th1 and Th17 cells. Our work reveals that TL1A plays a regulatory role in inflammatory bowel disease pathogenesis.

Identification of a novel role for TL1A/DR3 deficiency in acute respiratory distress syndrome that exacerbates alveolar epithelial disruption.

Alveolar epithelial barrier is a potential therapeutic target for acute respiratory distress syndrome (ARDS). However, an effective intervention against alveolar epithelial barrier has not been developed. Here, based on single-cell RNA and mRNA sequencing results, death receptor 3 (DR3) and its only known ligand tumor necrosis factor ligand-associated molecule 1A (TL1A) were significantly reduced in epithelium from an ARDS mice and cell models. The apparent reduction in the TL1A/DR3 axis in lungs from septic-ARDS patients was correlated with the severity of the disease. The examination of knockout (KO) and alveolar epithelium conditional KO (CKO) mice showed that TL1A deficiency exacerbated alveolar inflammation and permeability in lipopolysaccharide (LPS)-induced ARDS. Mechanistically, TL1A deficiency decreased glycocalyx syndecan-1 and tight junction-associated zonula occludens 3 by increasing cathepsin E level for strengthening cell-to-cell permeability. Additionally, DR3 deletion aggravated barrier dysfunction and pulmonary edema in LPS-induced ARDS through the above mechanisms based on the analyses of DR3 CKO mice and DR3 overexpression cells. Therefore, the TL1A/DR3 axis has a potential value as a key therapeutic signaling for the protection of alveolar epithelial barrier.

Hypomethylation of Tumor necrosis factor-like cytokine 1A(TL1A) and its decoy receptor 3 expressive level increase has diagnostic value in HBV-associated cirrhosis.

For patients with cirrhosis, early diagnosis is the key to delaying the development of liver fibrosis and improving prognosis. This study aimed to investigate the clinical significance of TL1A, which is a susceptibility gene for hepatic fibrosis, and DR3 in the development of cirrhosis and fibrosis. We analyzed the expression of TL1A, DR3, and other inflammatory cytokines associated with liver fibrosis in serum and PBMCs in 200 patients.TL1A methylation level was lower in patients with HBV-associated LC than in the other groups. In addition, the mRNA level and serum of TL1A and DR3 expression levels were found to increase in the LC. Hypomethylation of the TL1A promoter is present in HBV-associated LC, and TL1A and DR3 are highly expressed in HBV-associated cirrhosis. These results indicate that TL1A and DR3 may play an important role in the pathogenesis of LC and TL1A methylation levels may serve as a noninvasive biomarker for early diagnosis and progression of LC.

Genetic architecture of the inflammatory bowel diseases across East Asian and European ancestries.

Inflammatory bowel diseases (IBDs) are chronic disorders of the gastrointestinal tract with the following two subtypes: Crohn's disease (CD) and ulcerative colitis (UC). To date, most IBD genetic associations were derived from individuals of European (EUR) ancestries. Here we report the largest IBD study of individuals of East Asian (EAS) ancestries, including 14,393 cases and 15,456 controls. We found 80 IBD loci in EAS alone and 320 when meta-analyzed with ~370,000 EUR individuals (~30,000 cases), among which 81 are new. EAS-enriched coding variants implicate many new IBD genes, including ADAP1 and GIT2. Although IBD genetic effects are generally consistent across ancestries, genetics underlying CD appears more ancestry dependent than UC, driven by allele frequency (NOD2) and effect (TNFSF15). We extended the IBD polygenic risk score (PRS) by incorporating both ancestries, greatly improving its accuracy and highlighting the importance of diversity for the equitable deployment of PRS.

Integrated Analysis of Transcriptome Changes in Osteoarthritis: Gene Expression, Pathways and Alternative Splicing.

OBJECTIVE: Osteoarthritis (OA) is the most prevalent joint disease characterized by the degeneration of articular cartilage and the remodeling of its underlying bones, resulting in pain and loss of function in the knees and hips. As far as we know, no curative treatments are available except for the joint replacement. The precise molecular mechanisms which are involved in the degradation of cartilage matrix and development of osteoarthritis are still unclear. DESIGN: By analyzing RNA-seq data, we found the molecular changes at the transcriptome level such as alternative splicing, gene expression, and molecular pathways in OA knees cartilage. RESULTS: Expression analysis have identified 457 differential expressed genes including 266 up-regulated genes such as TNFSF15, ST6GALNAC5, TGFBI, ASPM, and TYM, and 191 down-regulated genes such as ADM, JUN, IRE2, PIGA, and MAFF. Gene set enrichment analysis (GSEA) analysis identified down-regulated pathways related to translation, transcription, immunity, PI3K/AKT, and circadian as well as disturbed pathways related to extracellular matrix and collagen. Splicing analysis identified 442 differential alternative splicing events within 284 genes in osteoarthritis, including genes involved in extracellular matrix (ECM) and alternative splicing, and TIA1 was identified as a key regulator of these splicing events. CONCLUSIONS: These findings provide insights into disease etiology, and offer favorable information to support the development of more effective interventions in response to the global clinical challenge of osteoarthritis.

Trans-ancestry, Bayesian meta-analysis discovers 20 novel risk loci for inflammatory bowel disease in an African American, East Asian and European cohort.

Inflammatory bowel disease (IBD) is an immune-mediated chronic intestinal disorder with major phenotypes: ulcerative colitis (UC) and Crohn's disease (CD). Multiple studies have identified over 240 IBD susceptibility loci. However, most studies have centered on European (EUR) and East Asian (EAS) populations. The prevalence of IBD in non-EUR, including African Americans (AAs), has risen in recent years. Here we present the first attempt to identify loci in AAs using a trans-ancestry Bayesian approach (MANTRA) accounting for heterogeneity between diverse ancestries while allowing for the similarity between closely related populations. We meta-analyzed genome-wide association studies (GWAS) and Immunochip data from a 2015 EUR meta-analysis of 38 155 IBD cases and 48 485 controls and EAS Immunochip study of 2824 IBD cases and 3719 controls, and our recent AA IBD GWAS of 2345 cases and 5002 controls. Across the major IBD phenotypes, we found significant evidence for 92% of 205 loci lead SNPs from the 2015 meta-analysis, but also for three IBD loci only established in latter studies. We detected 20 novel loci, all containing immunity-related genes or genes with other evidence for IBD or immune-mediated disease relevance: PLEKHG5;TNFSFR25 (encoding death receptor 3, receptor for TNFSF15 gene product TL1A), XKR6, ELMO1, BC021024;PI4KB;PSMD4 and APLP1 for IBD; AUTS2, XKR6, OSER1, TET2;AK094561, BCAP29 and APLP1 for CD; and GABBR1;MOG, DQ570892, SPDEF;ILRUN, SMARCE1;CCR7;KRT222;KRT24;KRT25, ANKS1A;TCP11, IL7, LRRC18;WDFY4, XKR6 and TNFSF4 for UC. Our study highlights the value of combining low-powered genomic studies from understudied populations of diverse ancestral backgrounds together with a high-powered study to enable novel locus discovery, including potentially important therapeutic IBD gene targets.

Case-case genome-wide association analysis identifying genetic loci with divergent effects on Crohn's disease and ulcerative colitis.

Crohn's disease (CD) and ulcerative colitis (UC), two major subtypes of inflammatory bowel disease, show substantial differences in their clinical course and treatment response. To identify the genetic factors underlying the distinct characteristics of these two diseases, we performed a genome-wide association study (GWAS) between CD (n = 2359) and UC (n = 2175) in a Korean population, followed by replication in an independent sample of 772 CD and 619 UC cases. Two novel loci were identified with divergent effects on CD and UC: rs9842650 in CD200 and rs885026 in NCOR2. In addition, the seven established susceptibility loci [major histocompatibility complex (MHC), TNFSF15, OTUD3, USP12, IL23R, FCHSD2 and RIPK2] reached genome-wide significance. Of the nine loci, six (MHC, TNFSF15, OTUD3, USP12, IL23R and CD200) were replicated in the case-case GWAS of European populations. The proportion of variance explained in CD-UC status by polygenic risk score analysis was up to 22.6%. The area under the receiver-operating characteristic curve value was 0.74, suggesting acceptable discrimination between CD and UC. This CD-UC GWAS provides new insights into genetic differences between the two diseases with similar symptoms and might be useful in improving their diagnosis and treatment.

A stable, engineered TL1A ligand co-stimulates T cells via specific binding to DR3.

TL1A (TNFSF15) is a TNF superfamily ligand which can bind the TNFRSF member death receptor 3 (DR3) on T cells and the soluble decoy receptor DcR3. Engagement of DR3 on CD4+ or CD8+ effector T cells by TL1A induces downstream signaling, leading to proliferation and an increase in secretion of inflammatory cytokines. We designed a stable recombinant TL1A molecule that (1) displays high monodispersity and stability, (2) displays the ability to activate T cells in vitro and in vivo, and (3) lacks binding to DcR3 while retaining functional activity via DR3. Together these results suggest the TL1A ligand can be amenable to therapeutic development on its own or paired with a tumor-targeting moiety.

Role of TNFSF15 variants in oral cancer development and clinicopathologic characteristics.

Tumour necrosis family superfamily (TNFSF) member 15 (TNFSF15), encoded by TNFSF15, regulates immune responses and inflammation. However, the roles of TNFSF15 single-nucleotide variants (SNVs; formerly SNPs) in oral cavity squamous cell carcinoma (OCSCC) remain unclear. This case-control study included 2523 participants (1324 patients with OCSCC [52.5%] and 1199 healthy controls [47.5%]). The effects of TNFSF15 rs3810936, rs6478108 and rs6478109 on cancer development and prognosis were analysed by real-time PCR genotype assay. The Genotype-Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA) databases were used to validate our findings. The results demonstrated that the patients with altered TNFSF15 SNVs had poorer histological differentiation than did those with wild-type alleles. TNFSF15 SNVs were significantly associated with moderate-to-poor histological differentiation in univariate logistic regression. In the GTEx database, the expression of altered TNFSF15 SNVs in whole blood was lower than that of wild-type alleles. However, the expression of altered SNVs in the upper aerodigestive mucosa was higher than that of wild-type alleles. In the TCGA database, the patients with higher TNFSF15 expression had shorter overall survival than did those with lower TNFSF15 expression, especially for human papillomavirus-negative and advanced staging groups. In conclusion, although TNFSF15 SNVs did not affect OCSCC development, the patients with altered TNFSF15 SNVs exhibited poorer histological differentiation. The patients with higher TNFSF15 expression had poorer prognosis than did those with lower TNFSF15 expression.

Investigation of Biomarkers Associated with Low Platelet Counts in Normal Karyotype Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) patients are at risk of bleeding due to disease-related lack of platelets and systemic coagulopathy. Platelets play a role in hemostasis. Leukemic blasts have been shown to alter platelet activation in vitro. Here we investigated biomarkers associated with thrombocytopenia in normal karyotype AML (NK-AML). From The Cancer Genome Atlas database, case-control study was performed between normal karyotype (NK) platelet-decreased AML (PD-AML, platelet count < 100 × 109/L, n = 24) and NK platelet-not-decreased AML (PND-AML, with platelet count ≥ 100 × 109/L, n = 13). Differentially expressed gene analysis, pathway analysis and modelling for predicting platelet decrease in AML were performed. DEG analysis and pathway analysis revealed 157 genes and eight pathways specific for PD-AML, respectively. Most of the eight pathways were significantly involved in G-protein-coupled receptor-related pathway, cytokine-related pathway, and bone remodeling pathway. Among the key genes involved in at least one pathway, three genes including CSF1R, TNFSF15 and CLEC10A were selected as promising biomarkers for predicting PD-AML (0.847 of AUC in support vector machine model). This is the first study that identified biomarkers using RNA expression data analysis and could help understand the pathophysiology in AML with low platelet count.

Identification of shared loci associated with both Crohn's disease and leprosy in East Asians.

Genome-wide association studies (GWAS) of Crohn's disease (CD) in European and leprosy in Chinese population have shown that CD and leprosy share genetic risk loci. As these shared loci were identified through cross-comparisons across different ethnic populations, we hypothesized that meta-analysis of GWAS on CD and leprosy in East Asian populations would increase power to identify additional shared loci. We performed a cross-disease meta-analysis of GWAS data from CD (1621 cases and 4419 controls) and leprosy (2901 cases 3801 controls) followed by replication in additional datasets comprising 738 CD cases and 488 controls and 842 leprosy cases and 925 controls. We identified one novel locus at 7p22.3, rs77992257 in intron 2 of ADAP1, shared between CD and leprosy with genome-wide significance (P = 3.80 × 10-11) and confirmed 10 previously established loci in both diseases: IL23R, IL18RAP, IL12B, RIPK2, TNFSF15, ZNF365-EGR2, CCDC88B, LACC1, IL27, NOD2. Phenotype variance explained by the polygenic risk scores derived from Chinese leprosy data explained up to 5.28% of variance of Korean CD, supporting similar genetic structures between the two diseases. Although CD and leprosy shared a substantial number of genetic susceptibility loci in East Asians, the majority of shared susceptibility loci showed allelic effects in the opposite direction. Investigation of the genetic correlation using cross-trait linkage disequilibrium score regression also showed a negative genetic correlation between CD and leprosy (rg [SE] = -0.40[0.13], P = 2.6 × 10-3). These observations implicate the possibility that CD might be caused by hyper-sensitive reactions toward pathogenic stimuli.

TL1A/DR3 Axis, A Key Target of TNF-a, Augments the Epithelial-Mesenchymal Transformation of Epithelial Cells in OVA-Induced Asthma.

Tumor necrosis factor (TNF)-like cytokine 1A (TL1A), a member of the TNF family, exists in the form of membrane-bound (mTL1A) and soluble protein (sTL1A). TL1A binding its only known functional receptor death domain receptor 3 (DR3) affects the transmission of various signals. This study first proposed that the TL1A/DR3 axis was significantly upregulated in patients and mice with both asthma and high TNF-a expression and in TNF-a-stimulated epithelial Beas-2B cells. Two independent approaches were used to demonstrate that the TL1A/DR3 axis of mice was strongly correlated with TNF-a in terms of exacerbating asthmatic epithelial-mesenchymal transformation (EMT). First, high expression levels of EMT proteins (e.g., collagen I, fibronectin, N-cadherin, and vimentin) and TL1A/DR3 axis were observed when mice airways were stimulated by recombinant mouse TNF-a protein. Moreover, EMT protein and TL1A/DR3 axis expression synchronously decreased after mice with OVA-induced asthma were treated with infliximab by neutralizing TNF-a activity. Furthermore, the OVA-induced EMT of asthmatic mice was remarkably improved upon the deletion of the TL1A/DR3 axis by knocking out the TL1A gene. TL1A siRNA remarkably intervened EMT formation induced by TNF-a in the Beas-2B cells. In addition, EMT was induced by the addition of high concentrations of recombinant human sTL1A with the cell medium. The TL1A overexpression via pc-mTL1A in vitro remarkably increased the EMT formation induced by TNF-a. Overall, these findings indicate that the TL1A/DR3 axis may have a therapeutic role for asthmatic with high TNF-a level.

An updated view of the pathogenesis of steroid-sensitive nephrotic syndrome.

Idiopathic nephrotic syndrome is the most common childhood glomerular disease. Most forms of this syndrome respond to corticosteroids at standard doses and are, therefore, defined as steroid-sensitive nephrotic syndrome (SSNS). Immunological mechanisms and subsequent podocyte disorders play a pivotal role in SSNS and have been studied for years; however, the precise pathogenesis remains unclear. With recent advances in genetic techniques, an exhaustive hypothesis-free approach called a genome-wide association study (GWAS) has been conducted in various populations. GWASs in pediatric SSNS peaked in the human leukocyte antigen class II region in various populations. Additionally, an association of immune-related CALHM6/FAM26F, PARM1, BTNL2, and TNFSF15 genes, as well as NPHS1, which encodes nephrin expressed in podocytes, has been identified as a locus that achieves genome-wide significance in pediatric SSNS. However, the specific mechanism of SSNS development requires elucidation. This review describes an updated view of SSNS pathogenesis from immunological and genetic aspects, including interactions with infections or allergies, production of circulating factors, and an autoantibody hypothesis.

Genome-wide association study identifies TNFSF15 associated with childhood asthma.

BACKGROUND: Genome-wide association studies (GWASs) of asthma have identified several risk alleles and loci, but most have been conducted in individuals with European-ancestry. Studies in Asians, especially children, are still lacking. We aimed to identify susceptibility loci by performing the first GWAS of asthma in Korean children with persistent asthma. METHODS: We used a discovery set of 741 children with persistent asthma as cases and 589 healthy children and 551 healthy adults as controls to perform a GWAS. We validated our GWAS findings using UK Biobank data. We then used the Genotype-Tissue Expression database to identify expression quantitative trait loci of candidate variants. Finally, we quantified proteins of genes associated with asthma. RESULTS: Variants at the 17q12-21 locus and SNPs in CYBRD1 and TNFSF15 genes were associated with persistent childhood asthma at genome-wide thresholds of significance. Four SNPs in the TNFSF15 gene were also associated with childhood-onset asthma in British white participants in the UK Biobank data. The asthma-associated rs7856856-C allele, the lead SNP, was associated with decreased TNFSF15 expression in whole blood and in arteries. Korean children with asthma had lower serum TNFSF15 levels than controls, and those with the asthma risk rs7856856-CC genotype exhibited the lowest serum TNFSF15 levels overall, especially asthmatic children. CONCLUSIONS: Our GWAS of persistent childhood asthma with allergic sensitization identified a new susceptibility gene, TNFSF15, and replicated associations at the 17q12-21 childhood-onset asthma locus. This novel association may be mediated by reduced expression of serum TNFSF15 and loss of suppression of angiogenesis.

Antitumor Necrosis Factor-like Ligand 1A Therapy Targets Tissue Inflammation and Fibrosis Pathways and Reduces Gut Pathobionts in Ulcerative Colitis.

BACKGROUND: The first-in-class treatment PF-06480605 targets the tumor necrosis factor-like ligand 1A (TL1A) molecule in humans. Results from the phase 2a TUSCANY trial highlighted the safety and efficacy of PF-06480605 in ulcerative colitis. Preclinical and in vitro models have identified a role for TL1A in both innate and adaptive immune responses, but the mechanisms underlying the efficacy of anti-TL1A treatment in inflammatory bowel disease (IBD) are not known. METHODS: Here, we provide analysis of tissue transcriptomic, peripheral blood proteomic, and fecal metagenomic data from the recently completed phase 2a TUSCANY trial and demonstrate endoscopic improvement post-treatment with PF-06480605 in participants with ulcerative colitis. RESULTS: Our results revealed robust TL1A target engagement in colonic tissue and a distinct colonic transcriptional response reflecting a reduction in inflammatory T helper 17 cell, macrophage, and fibrosis pathways in patients with endoscopic improvement. Proteomic analysis of peripheral blood revealed a corresponding decrease in inflammatory T-cell cytokines. Finally, microbiome analysis showed significant changes in IBD-associated pathobionts, Streptococcus salivarius, S. parasanguinis, and Haemophilus parainfluenzae post-therapy. CONCLUSIONS: The ability of PF-06480605 to engage and inhibit colonic TL1A, targeting inflammatory T cell and fibrosis pathways, provides the first-in-human mechanistic data to guide anti-TL1A therapy for the treatment of IBD.

TNFSF15 Promotes Antimicrobial Pathways in Human Macrophages and These Are Modulated by TNFSF15 Disease-Risk Variants.

BACKGROUND & AIMS: TNFSF15 genetic variants leading to increased TNF superfamily member 15 (TNFSF15) expression confer risk for inflammatory bowel disease (IBD), and TNFSF15 is being explored as a therapeutic target in IBD patients. Although the focus for TNFSF15-mediated inflammatory outcomes has been predominantly on its action on T cells, TNFSF15 also promotes inflammatory outcomes in human macrophages. Given the critical role for macrophages in bacterial clearance, we hypothesized that TNFSF15 promotes antimicrobial pathways in human macrophages and that macrophages from TNFSF15 IBD risk carriers with higher TNFSF15 expression have an advantage in these antimicrobial outcomes. METHODS: We analyzed protein expression, signaling, bacterial uptake, and intracellular bacterial clearance in human monocyte-derived macrophages through flow cytometry, enzyme-linked immunosorbent assay, and gentamicin protection. RESULTS: Autocrine/paracrine TNFSF15 interactions with death receptor 3 (DR3) were required for optimal levels of pattern-recognition-receptor (PRR)-induced bacterial clearance in human macrophages. TNFSF15 induced pyruvate dehydrogenase kinase 1-dependent bacterial uptake and promoted intracellular bacterial clearance through reactive oxygen species, nitric oxide synthase 2, and autophagy up-regulation. The TNFSF15-initiated TNF receptor-associated factor 2/receptor-interacting protein kinase 1/RIP3 pathway was required for mitogen-activated protein kinase and nuclear factor-κB activation, and, in turn, induction of each of the antimicrobial pathways; the TNFSF15-initiated Fas-associated protein with death domain/mucosa-associated lymphoid tissue lymphoma translocation protein 1/caspase-8 pathway played a less prominent role in antimicrobial functions, despite its key role in TNFSF15-induced cytokine secretion. Complementation of signaling pathways or antimicrobial pathways restored bacterial uptake and clearance in PRR-stimulated macrophages where TNFSF15:DR3 interactions were inhibited. Monocyte-derived macrophages from high TNFSF15-expressing rs6478108 TT IBD risk carriers in the TNFSF15 region showed increased levels of the identified antimicrobial pathways. CONCLUSIONS: We identify that autocrine/paracrine TNFSF15 is required for optimal PRR-enhanced antimicrobial pathways in macrophages, define mechanisms regulating TNFSF15-dependent bacterial clearance, and determine how the TNFSF15 IBD risk genotype modulates these outcomes.

Direct signaling of TL1A-DR3 on fibroblasts induces intestinal fibrosis in vivo.

Tumor necrosis factor-like cytokine 1A (TL1A, TNFSF15) is implicated in inflammatory bowel disease, modulating the location and severity of inflammation and fibrosis. TL1A expression is increased in inflamed mucosa and associated with fibrostenosing Crohn's disease. Tl1a-overexpression in mice causes spontaneous ileitis, and exacerbates induced proximal colitis and fibrosis. Intestinal fibroblasts express Death-receptor 3 (DR3; the only know receptor for TL1A) and stimulation with TL1A induces activation in vitro. However, the contribution of direct TL1A-DR3 activation on fibroblasts to fibrosis in vivo remains unknown. TL1A overexpressing naïve T cells were transferred into Rag-/- , Rag-/- mice lacking DR3 in all cell types (Rag-/-Dr3-/-), or Rag-/- mice lacking DR3 only on fibroblasts (Rag-/-Dr3∆Col1a2) to induce colitis and fibrosis, assessed by clinical disease activity index, intestinal inflammation, and collagen deposition. Rag-/- mice developed overt colitis with intestinal fibrostenosis. In contrast, Rag-/-Dr3-/- demonstrated decreased inflammation and fibrosis. Despite similar clinical disease and inflammation as Rag-/-, Rag-/-Dr3∆Col1a2 exhibited reduced intestinal fibrosis and attenuated fibroblast activation and migration. RNA-Sequencing of TL1A-stimulated fibroblasts identified Rho signal transduction as a major pathway activated by TL1A and inhibition of this pathway modulated TL1A-mediated fibroblast functions. Thus, direct TL1A signaling on fibroblasts promotes intestinal fibrosis in vivo. These results provide novel insight into profibrotic pathways mediated by TL1A paralleling its pro-inflammatory effects.

Polymorphism rs6478109 in the TNFSF15 gene contributes to the susceptibility to Crohn's disease but not ulcerative colitis: a meta-analysis.

OBJECTIVE: Polymorphisms in the tumor necrosis factor superfamily 15 (TNFSF15) gene contribute to susceptibility to inflammatory bowel disease (IBD). However, associations between TNFSF15 rs6478109, rs7869487, and rs7865494 polymorphisms and IBD remain unclear. METHODS: Eligible articles were retrieved from the PubMed, EMBASE, Web of Science, and CNKI databases through 20 March 2020. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to evaluate the relationships of TNFSF15 polymorphisms with IBD susceptibility. RESULTS: Under the recessive model, TNFSF15 rs6478109 was associated with IBD risk (OR = 0.56; 95% CI: 0.35, 0.92). Stratification analyses based on the type of disease-Crohn's disease (CD) or ulcerative colitis (UC)-revealed a significant association under the allelic and recessive models between TNFSF15 rs6478109 and CD (allelic model: OR = 0.84, 95% CI: 0.71, 0.99; recessive model: OR = 0.44, 95% CI: 0.22, 0.87) but not UC. Stratification by ethnicity indicated a significantly decreased risk of IBD in Asian populations with TNFSF15 rs6478109 under the recessive model (OR = 0.56, 95% CI: 0.35, 0.92). CONCLUSIONS: Our meta-analysis suggested that under the allelic and recessive models, the TNFSF15 rs6478109 polymorphism was likely protective for CD but not UC in the Asian population.