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

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

  • Mucosal Immunol. 2022 Feb;15(2):327-337. doi: 10.1038/s41385-021-00472-w.
Mario C Manresa 1 2 3,  Amanda Wu 1 2,  Quan M Nhu 1 2 4,  Austin W T Chiang 1,  Kevin Okamoto 1,  Haruka Miki 3,  Richard Kurten 5,  Elaine Pham 1 2,  Loan D Duong 1 2,  Nathan E Lewis 1,  Praveen Akuthota 6,  Michael Croft 3 7,  Seema S Aceves 8 9 10 11
Affiliations

Affiliations

  • 1 Department of Pediatrics, University of California, San Diego, CA, USA.
  • 2 Division of Allergy Immunology, San Diego, CA, USA.
  • 3 La Jolla Institute for Immunology, La Jolla, CA, USA.
  • 4 Division of Gastroenterology and Hepatology, Scripps Clinic, San Diego, CA, USA.
  • 5 Department of Physiology and Biophysics, University of Arkansas for Medical Sciences, Arkansas Children's Hospital Research Institute, Little Rock, AR, USA.
  • 6 Division of Pulmonary, Critical Care, and Sleep Medicine, University of California San Diego, La Jolla, CA, USA.
  • 7 Department of Medicine, University of California, San Diego, CA, USA.
  • 8 Department of Pediatrics, University of California, San Diego, CA, USA. saceves@health.ucsd.edu.
  • 9 Division of Allergy Immunology, San Diego, CA, USA. saceves@health.ucsd.edu.
  • 10 Department of Medicine, University of California, San Diego, CA, USA. saceves@health.ucsd.edu.
  • 11 Rady Children's Hospital San Diego, San Diego, CA, USA. saceves@health.ucsd.edu.
PMID: 34903876 DOI: 10.1038/s41385-021-00472-w
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.

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