Chemical Chaperones Mitigate Experimental Asthma by Attenuating Endoplasmic Reticulum Stress

Abstract

Endoplasmic reticulum (ER) stress and consequent unfolded protein response (UPR) are important in inflammation but have been poorly explored in asthma. We used a mouse model of allergic airway inflammation (AAI) with features of asthma to understand the role of ER stress and to explore potential therapeutic effects of inhaled chemical chaperones, which are small molecules that can promote protein folding and diminish UPR. UPR markers were initially measured on alternate days during a 7-day daily allergen challenge model. UPR markers increased within 24 hours after the first allergen challenge and peaked by the third challenge, before AAI was fully established (from the fifth challenge onward). Three chemical chaperones-glycerol, trehalose, and trimethylamine-N-oxide (TMAO)-were initially administered during allergen challenge (preventive regimen). TMAO, the most effective of these chemical chaperones and 4-phenylbutyric acid, a chemical chaperone currently in clinical trials, were further tested for potential therapeutic activities after AAI was established (therapeutic regimen). Chemical chaperones showed a dose-dependent reduction in UPR markers, airway inflammation, and remodeling in both regimens. Our results indicate an early and important role of the ER stress pathway in asthma pathogenesis and show therapeutic potential for chemical chaperones.

Interaction between endoplasmic/sarcoplasmic reticulum stress (ER/SR stress), mitochondrial signaling and Ca2+ regulation in airway smooth muscle (ASM)

“…Recently, ER/SR stress markers have been identified in lungs from mouse models of airway diseases and chemical chaperones. Inhibition of ER/SR stress responses successfully reduced airway inflammation and airway hyper-reactivity observed in those models (Hoffman et al 2013; Kim et al 2013; Makhija et al 2013). The results of our studies on hASM cells support a central role of inflammatory cytokine-induced ER/SR stress in both the enhanced contractile response of ASM (hyper-reactive state) and the increase in ASM cell proliferation (synthetic state) (Fig.…”

“…A recent study (Makhija et al 2013) showed that there is an increased expression of ER/SR stress protein markers such as BiP/GRP-78 and ATF6 in lungs from an ovalbumin (OVA) sensitized mouse model of asthma, and that chemical chaperone treatment used to attenuate ER/SR stress is effective in reducing airway remodeling and inflammation. Others recent studies confirmed the presence of ER/SR stress markers in the OVA mouse model (Kim et al 2013) as well as another mouse model of asthma: house dust mite sensitization (Hoffman et al 2013).…”

Endoplasmic Reticulum Stress in Immunity

“…IRE1α-or IRE1β-mediated XBP-1 activation may sustain the enhanced ER calcium stores frequently observed in inflamed airway mucosa (209), as well as the IL-13-driven excessive airway epithelial mucus production observed in allergic airway disease. However, a recent study demonstrated that chemical chaperones dose-dependently reduce UPR gene expression and inflammatory markers (210). Robust genetic studies will be critical to confidently determine whether and how the observed UPR activation contributes to inflammatory …”

TMAO: A small molecule of great expectations

“…Furthermore, TMAO has been found to protect epidermolysis bullosa simplex keratinocytes from heat stressinduced keratin aggregation, which implies the therapeutic potential of TMAO in epidermolysis M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT 15 bullosa and other keratinopathies [85]. Other potential therapeutic applications of TMAO include corneal dystrophies [86], cataract [87], glaucoma [88], asthma [89] or Machado-Joseph disease/spinocerebellar ataxia-3 (MJD/SCA-3) [90].…”