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A7162 - REV-ERB Alpha Augments House Dust Mite Induced Allergic Asthma Via Regulation of Thymic Stromal Lymphopoietin (TSLP)
Author Block: I. Sundar1, M. T. Sellix2, S. N. Georas3, I. Rahman1; 1Environmental Medicine, University of Rochester Medical Center, Rochester, NY, United States, 2Medicine, Division of Endocrinology and Metabolism, University of Rochester Medical Center, Rochester, NY, United States, 3Medicine, Pulmonary Critical Care Medicine, University of Rochester Medical Center, Rochester, NY, United States.
Rationale: Allergic asthma is a chronic inflammatory disease and asthma attacks, particularly in response to household allergens like House Dust Mite (HDM), show a daily variation in occurrence and severity with most severe attacks occurring in the early morning. The molecular clock that drives internal rhythms, including the nuclear receptor Rev-erbα, plays a role in lung inflammatory responses by maintaining tissue specific genetic programs of clock-controlled genes (CCGs) critical for immune-inflammatory responses. Though not an established clock target gene, Thymic stromal lymphopoietin (TSLP) has been identified as a regulator for allergic airway inflammation, known to influence the production of T helper type 2 (Th2) cytokines from mast cells. Intriguingly, the impact of allergen-induced dysfunction on the clock and its putative target genes, including TSLP, and the role of clock disruption in gating the severity of inflammatory responses during asthma remain unclear. We hypothesize that allergen-induced disruption of REV-ERBα expression leads to irregular clock function in the lungs, altered TSLP activity and augmented immune-inflammatory responses. Methods: Wild-type (BALB/c or C57BL/6J) and Rev-erbα KO mice (congenic C57BL/6J) were exposed to acute HDM allergen challenge. Mice were administered PBS or HDM extract intra-nasally for 10 days. Mice were euthanized 48 hours after the last challenge at two different time points (am and pm). We measured the severity of asthmatic lung phenotypes including airway inflammation and hyper-responsiveness, Th2 cytokines in bronchoalveolar lavage (BAL) fluid, plasma IgE/IgG, mucous metaplasia, abundance of Muc5ac and Muc5b protein, mucin and CCG expression in the lungs. Results: WT mice exposed to HDM show reduced expression of REV-ERBα in airway epithelium associated with increased airway inflammation, airway hyper-responsiveness, elevated Th2 cytokine levels, increased plasma IgE/IgG, mucous metaplasia, increased abundance of Muc5ac/Muc5b and diminished expression of clock and CCG mRNA (Clock, Bmal1, Nr1d1 (Rev-erbα), Nr1d2, Per1, Per2, Cry1,Cry2) in the lungs. Rev-erbα KO mice displayed a significantly greater airway inflammation in response to HDM, increased TSLP expression, elevated Th2 cytokine levels and mucous metaplasia. Notably, treatment with a selective Rev-erbα agonist in WT mice attenuated the response to HDM. Conclusion: Our data from a mouse model of allergic asthma suggest that the clock protein and nuclear receptor REV-ERBα contributes to the etiology and pathophysiology of allergic asthma via TSLP activation. Thus, we have identified REV-ERBα as a putative novel target, and potential use of REV-ERBα agonist might be useful for alleviating the time-dependent immune-inflammatory response in allergic asthma.