MyD88 regulates a prolonged adaptation response to environmental dust exposure-induced lung disease

• Published in: Respiratory research Vol. 21; no. 1; pp. 97 - 14
• Main Authors: Johnson, Amber N, Harkema, Jack R, Nelson, Amy J, Dickinson, John D, Kalil, Julianna, Duryee, Michael J, Thiele, Geoffrey M, Kumar, Balawant, Singh, Amar B, Gaurav, Rohit, Glover, Sarah C, Tang, Ying, Romberger, Debra J, Kielian, Tammy, Poole, Jill A
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 22.04.2020; BioMed Central; BMC
• Subjects: Adaptation; Adaptation, Physiological - physiology; Agriculture; Airway inflammation; Animals; Asthma; Bronchitis; Care and treatment; Chemokines; Chronic obstructive pulmonary disease; Cytokines; Development and progression; Disease; Dust; Environmental Exposure - adverse effects; Environmental respiratory and skin disease; Exposure; Female; Genetic aspects; Health aspects; Immune response; Immunoglobulin E; Inflammation; Inflammatory response; Inhalation Exposure - adverse effects; Interleukin 10; Laboratories; Lavage; Lung diseases; Lung Diseases - chemically induced; Lung Diseases - metabolism; Lungs; Lymphocytes; Lymphocytes B; Male; Metaplasia; Mice; Mice, Inbred C57BL; Mice, Knockout; MyD88 protein; Myeloid Differentiation Factor 88 - metabolism; Neutrophils; Occupational; Occupational diseases; Organic dust; Particulate matter; Proteins; Respiratory tract diseases; Toll-like receptors; United States; Minneapolis Minnesota; United States > US; Organic dust; Airway inflammation; Occupational; Environmental respiratory and skin disease; Agriculture; MyD88; Adaptation
• ISSN: 1465-993X; 1465-9921; 1465-993X; 1465-9921
• DOI: 10.1186/s12931-020-01362-8

Environmental organic dust exposures enriched in Toll-like receptor (TLR) agonists can reduce allergic asthma development but are associated with occupational asthma and chronic bronchitis. The TLR adaptor protein myeloid differentiation factor88 (MyD88) is fundamental in regulating acute inflammatory responses to organic dust extract (ODE), yet its role in repetitive exposures is unknown and could inform future strategies. Wild-type (WT) and MyD88 knockout (KO) mice were exposed intranasally to ODE or saline daily for 3 weeks (repetitive exposure). Repetitively exposed animals were also subsequently rested with no treatments for 4 weeks followed by single rechallenge with saline/ODE. Repetitive ODE exposure induced neutrophil influx and release of pro-inflammatory cytokines and chemokines were profoundly reduced in MyD88 KO mice. In comparison, ODE-induced cellular aggregates, B cells, mast cell infiltrates and serum IgE levels remained elevated in KO mice and mucous cell metaplasia was increased. Expression of ODE-induced tight junction protein(s) was also MyD88-dependent. Following recovery and then rechallenge with ODE, inflammatory mediators, but not neutrophil influx, was reduced in WT mice pretreated with ODE coincident with increased expression of IL-33 and IL-10, suggesting an adaptation response. Repetitively exposed MyD88 KO mice lacked inflammatory responsiveness upon ODE rechallenge. MyD88 is essential in mediating the classic airway inflammatory response to repetitive ODE, but targeting MyD88 does not reduce mucous cell metaplasia, lymphocyte influx, or IgE responsiveness. TLR-enriched dust exposures induce a prolonged adaptation response that is largely MyD88-independent. These findings demonstrate the complex role of MyD88-dependent signaling during acute vs. chronic organic dust exposures.