Dataset Information

LIGHT controls distinct homeostatic and inflammatory gene expression profiles in esophageal fibroblasts via differential HVEM and LTβR-mediated mechanisms.

ABSTRACT: Fibroblasts mediate tissue remodeling in eosinophilic esophagitis (EoE), a chronic allergen-driven inflammatory pathology. Diverse fibroblast subtypes with homeostasis-regulating or inflammatory profiles have been recognized in various tissues, but which mediators induce these alternate differentiation states remain largely unknown. We recently identified that TNFSF14/LIGHT promotes an inflammatory esophageal fibroblast in vitro. Herein we used esophageal biopsies and primary fibroblasts to investigate the role of the LIGHT receptors, herpes virus entry mediator (HVEM) and lymphotoxin-beta receptor (LTβR), and their downstream activated pathways, in EoE. In addition to promoting inflammatory gene expression, LIGHT down-regulated homeostatic factors including WNTs, BMPs and type 3 semaphorins. In vivo, WNT2B⁺ fibroblasts were decreased while ICAM-1⁺ and IL-34⁺ fibroblasts were expanded in EoE, suggesting that a LIGHT-driven gene signature was imprinted in EoE versus normal esophageal fibroblasts. HVEM and LTβR overexpression and deficiency experiments demonstrated that HVEM regulates a limited subset of LIGHT targets, whereas LTβR controls all transcriptional effects. Pharmacologic blockade of the non-canonical NIK/p100/p52-mediated NF-κB pathway potently silenced LIGHT's transcriptional effects, with a lesser role found for p65 canonical NF-κB. Collectively, our results show that LIGHT promotes differentiation of esophageal fibroblasts toward an inflammatory phenotype and represses homeostatic gene expression via a LTβR-NIK-p52 NF-κB dominant pathway.

SUBMITTER: Manresa MC

PROVIDER: S-EPMC8866113 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

LIGHT controls distinct homeostatic and inflammatory gene expression profiles in esophageal fibroblasts via differential HVEM and LTβR-mediated mechanisms.

Manresa Mario C MC Wu Amanda A Nhu Quan M QM Chiang Austin W T AWT Okamoto Kevin K Miki Haruka H Kurten Richard R Pham Elaine E Duong Loan D LD Lewis Nathan E NE Akuthota Praveen P Croft Michael M Aceves Seema S SS

Mucosal immunology 20211213 2

Fibroblasts mediate tissue remodeling in eosinophilic esophagitis (EoE), a chronic allergen-driven inflammatory pathology. Diverse fibroblast subtypes with homeostasis-regulating or inflammatory profiles have been recognized in various tissues, but which mediators induce these alternate differentiation states remain largely unknown. We recently identified that TNFSF14/LIGHT promotes an inflammatory esophageal fibroblast in vitro. Herein we used esophageal biopsies and primary fibroblasts to inve ...[more]

PMID: 34903876

Similar Datasets

Project description:The herpesvirus entry mediator (HVEM) and its ligand LIGHT play crucial roles in immune system regulation, including T-cell proliferation, B-cell differentiation, and immunoglobulin secretion. However, excessive T-cell activation can lead to chronic inflammation and autoimmune diseases. Thus, inhibiting the HVEM-LIGHT interaction emerges as a promising therapeutic strategy for these conditions and in preventing adverse reactions in organ transplantation. This study focused on designing peptide inhibitors, targeting the HVEM-LIGHT interaction, using molecular dynamics (MD) simulations of 65 peptides derived from HVEM. These peptides varied in length and disulfide-bond configurations, crucial for their interaction with the LIGHT trimer. By simulating 31 HVEM domain variants, including the full-length protein, we assessed conformational changes upon LIGHT binding to understand the influence of HVEM segments and disulfide bonds on the binding mechanism. Employing multitrajectory microsecond-scale, all-atom MD simulations and molecular mechanics with generalized Born and surface area (MM-GBSA) binding energy estimation, we identified promising CRD2 domain variants with high LIGHT affinity. Notably, point mutations in these variants led to a peptide with a single disulfide bond (C58-C73) and a K54E substitution, exhibiting the highest binding affinity. The importance of the CRD2 domain and Cys58-Cys73 disulfide bond for interrupting HVEM-LIGHT interaction was further supported by analyzing truncated CRD2 variants, demonstrating similar binding strengths and mechanisms. Further investigations into the binding mechanism utilized steered MD simulations at various pulling speeds and umbrella sampling to estimate the energy profile of HVEM-based inhibitors with LIGHT. These comprehensive analyses revealed key interactions and different binding mechanisms, highlighting the increased binding affinity of selected peptide variants. Experimental circular dichroism techniques confirmed the structural properties of these variants. This study not only advances our understanding of the molecular basis of HVEM-LIGHT interactions but also provides a foundation for developing novel therapeutic strategies for immune-related disorders. Furthermore, it sets a gold standard for peptide inhibitor design in drug development due to its systematic approach.

Dataset Information

LIGHT controls distinct homeostatic and inflammatory gene expression profiles in esophageal fibroblasts via differential HVEM and LTβR-mediated mechanisms.

Publications

LIGHT controls distinct homeostatic and inflammatory gene expression profiles in esophageal fibroblasts via differential HVEM and LTβR-mediated mechanisms.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets