Effect of Epithelial-Specific MyD88 Signaling Pathway on Airway Inflammatory Response to Organic Dust Exposure

Authors

Amber N Johnson
John Dickinson
Amy Nelson
Rohit Gaurav
Katrina Kudrna
Scott E Evans
Katherine Janike
Todd A Wyatt
Jill A Poole

Publication Date

12-1-2023

Journal

Journal of Immunotoxicology

Abstract

The Toll-like receptor (TLR) adaptor protein MyD88 is integral to airway inflammatory response to microbial-enriched organic dust extract (ODE) exposures. ODE-induced airway neutrophil influx and release of pro-inflammatory cytokines was essentially abrogated in global MyD88-deficient mice, yet these mice demonstrate an increase in airway epithelial cell mucin expression. To further elucidate the role of MyD88-dependent responses specific to lung airway epithelial cells in response to ODE in vivo, the surfactant protein C protein (SPC) Cre+ embryologic expressing airway epithelial cells floxed for MyD88 to disrupt MyD88 signaling were utilized. The inducible club cell secretory protein (CCSP) Cre+, MyD88 floxed, were also developed. Using an established protocol, mice were intranasally instilled with ODE or saline once or daily up to 3 weeks. Mice with MyD88-deficient SPC+ lung epithelial cells exhibited decreased neutrophil influx following ODE exposure once and repetitively for 1 week without modulation of classic pro-inflammatory mediators including tumor necrosis factor (TNF)-α, interleukin (IL)-6, and neutrophil chemoattractants. This protective response was lost after 3 weeks of repetitive exposure. ODE-induced Muc5ac mucin expression at 1 week was also reduced in MyD88-deficient SPC+ cells. Acute ODE-induced IL-33 was reduced in MyD88-deficient SPC+ cells whereas serum IgE levels were increased at one week. In contrast, mice with inducible MyD88-deficient CCSP+ airway epithelial cells demonstrated no significant difference in experimental indices following ODE exposure. Collectively, these findings suggest that MyD88-dependent signaling targeted to all airway epithelial cells plays an important role in mediating neutrophil influx and mucin production in response to acute organic dust exposures.

Keywords

Animals, Mice, Myeloid Differentiation Factor 88, Inhalation Exposure, Signal Transduction, Interleukin-6, Toll-Like Receptors, Tumor Necrosis Factor-alpha, Dust, Mucins, Mice, Inbred C57BL

DOI

10.1080/1547691X.2022.2148782

PMID

36538286

PMCID

PMC9912912

PubMedCentral® Posted Date

12-1-2024

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes