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

Abstract

Background: 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. Methods: 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. Results: 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. Conclusions: 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.

Lipid-Sensing Receptor FFAR4 Modulates Pulmonary Epithelial Homeostasis following Immunogenic Exposures Independently of the FFAR4 Ligand Docosahexaenoic Acid (DHA)

“…Surprisingly, FFAR4 had a significant and independent effect on cell influx ( Figure 1 d) [ 1 , 2 ]. Entrapment of immune cells in the mesenchyme has been demonstrated in Myd88 -null mice repetitively exposed to DE [ 33 , 43 ]. These published studies revealed no significant changes to cells in the BAL but with significant histopathologic changes in the Myd88 -deficient mice, including immune cell entrapment and epithelial dysplasia.…”

“…In addition, epithelial progenitor populations in the lung also express H2k1 and drive barrier restoration [ 81 ]. Lymphocyte antigen 96 ( Ly96 ), also called myeloid differentiation factor 2 (Md2), dimerizes with TLR4 to recognize LPS and initiate MyD88 signaling cascades driving pro-inflammatory gene expression in response to swine dust exposure [ 33 , 82 , 83 ]. MyD88 KO mice repetitively exposed to DE exhibited significantly reduced chemokine and cytokine release, dampened BAL cell influx, and epithelial dysplasia.…”

“…To accomplish this aim, we employed a well-established mouse model of agricultural dust-induced lung inflammation and complemented these studies using additional exposure models known to facilitate lung damage through different mechanisms. Our mouse model of this dust exposure allows for the study of pulmonary inflammation and resolution, as these exposure models are self-limiting [ 33 , 34 ]. This study clarifies the impact of FFAR4 on the inflammatory process through repair, with the long-term objective of ultimately identifying potential therapeutics, such as against DHA and FFAR4, and interventions for chronic lung diseases, for which few current therapeutics are available.…”

Nrf2 Activation Protects Against Organic Dust and Hydrogen Sulfide Exposure Induced Epithelial Barrier Loss and K. pneumoniae Invasion

“…Organic dust extracts (ODE) from animal feeding operations induce a profound inflammatory response both in vitro and in vivo with several prior studies demonstrating strong roles for Toll-like receptor (TLR) and MyD88 signaling pathways ( Charavaryamath et al., 2005 ; Charavaryamath et al., 2008 ; Charavaryamath et al., 2008 ; Poole et al., 2015 ). In airway epithelial cells, these exposures induce pro-inflammatory cytokine release, neutrophil influx, mucus metaplasia, alter tight junction expressions, disrupt cellular migration, and slow ciliary beat frequency ( Wyatt et al., 2008 ; Bhat et al., 2019 ; Johnson et al., 2020 ; Shrestha et al., 2021 ). It has also been demonstrated that CO 2 concentrations differentially effect the magnitude of inflammatory responses to ODE and various TLR ligands ( Schneberger et al., 2015 ; Schneberger et al., 2021 ).…”

“…Previous work has shown that exposure to swine production units containing organic dust and H 2 S induces airway epithelial damage ( Charavaryamath et al., 2008 ). ODE is known to induce alterations in several tight junction components including occludin protein ( Johnson et al., 2020 ). However, the effect of simultaneous exposure to organic dust and H 2 S on the airway epithelial tight junction proteins is unknown.…”