Thymic stromal lymphopoietin protects in a model of airway damage and inflammation via regulation of caspase-1 activity and apoptosis inhibition

Mucosal Immunol. 2020 Jul;13(4):584-594. doi: 10.1038/s41385-020-0271-0. Epub 2020 Feb 26.

Abstract

Thymic stromal lymphopoietin (TSLP), an epithelial cell-derived cytokine, exhibits both pro-inflammatory and pro-homeostatic properties depending on the context and tissues in which it is expressed. It remains unknown whether TSLP has a similar dual role in the airways, where TSLP is known to promote allergic inflammation. Here we show that TSLP receptor (TSLPR)-deficient mice (Tslpr-/-) and mice treated with anti-TSLP antibodies exhibited increased airway inflammation and morbidity rates after bleomycin-induced tissue damage. We found that signaling through TSLPR on non-hematopoietic cells was sufficient for TSLP's protective function. Consistent with this finding, we showed that TSLP reduces caspase-1 and caspase-3 activity levels in primary human bronchial epithelial cells treated with bleomycin via Bcl-xL up-regulation. These observations were recapitulated in vivo by observing that Tslpr-/- mice showed reduced Bcl-xL expression that paralleled increased lung caspase-1 and caspase-3 activity levels and IL-1β concentrations in the bronchial-alveolar lavage fluid. Our studies reveal a novel contribution for TSLP in preventing damage-induced airway inflammation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Apoptosis / genetics
  • Biomarkers
  • Bleomycin / adverse effects
  • Caspase 1 / metabolism*
  • Caspase 3 / metabolism
  • Cytokines / pharmacology*
  • Disease Models, Animal
  • Disease Susceptibility
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism
  • Humans
  • Immunoglobulins / metabolism
  • Immunohistochemistry
  • Inflammation / drug therapy
  • Inflammation / etiology
  • Inflammation / metabolism
  • Mice
  • Mice, Knockout
  • Protective Agents / pharmacology*
  • Protein Binding
  • Receptors, Cytokine / metabolism
  • Respiratory Mucosa / drug effects*
  • Respiratory Mucosa / metabolism*
  • Respiratory Mucosa / pathology
  • Respiratory Tract Diseases / drug therapy
  • Respiratory Tract Diseases / etiology
  • Respiratory Tract Diseases / metabolism
  • Signal Transduction / drug effects
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocyte Subsets / metabolism
  • bcl-X Protein / genetics
  • bcl-X Protein / metabolism

Substances

  • Biomarkers
  • Cytokines
  • Immunoglobulins
  • Protective Agents
  • Receptors, Cytokine
  • Tslpr protein, mouse
  • bcl-X Protein
  • Bleomycin
  • Caspase 3
  • Caspase 1
  • thymic stromal lymphopoietin