1. Effect of epithelial-specific MyD88 signaling pathway on airway inflammatory response to organic dust exposure.
- Author
-
Johnson, Amber N., Dickinson, John, Nelson, Amy, Gaurav, Rohit, Kudrna, Katrina, Evans, Scott E., Janike, Katherine, Wyatt, Todd A., and Poole, Jill A.
- Subjects
MICROBIOLOGICAL aerosols ,LUNGS ,ENDOTOXINS ,MYELOID differentiation factor 88 ,IMMUNOGLOBULIN E ,TUMOR necrosis factors ,CELLULAR signal transduction ,AIRWAY (Anatomy) - 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 3weeks. Mice with MyD88-deficient SPC+ lung epithelial cells exhibited decreased neutrophil influx following ODE exposure once and repetitively for 1week without modulation of classic pro-inflammatory mediators including tumor necrosis factor (TNF)-a, interleukin (IL)-6, and neutrophil chemoattractants. This protective response was lost after 3weeks 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. [ABSTRACT FROM AUTHOR]- Published
- 2023
- Full Text
- View/download PDF