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House dust mite impairs IFN-β expression in response to viral stimuli and skews towards MLKL-mediated necroptosis in bronchial epithelial cells

Rationale: Deficient production of anti-viral interferon (IFN)-s may contribute to Rhinovirus (RV)-induced asthma exacerbations. However, the involved mechanisms are unclear. We have previously shown that IFN-s deficiency at exacerbation promotes necroptosis, a regulated cell death mechanism associated with inflammation (Cerps et al., 2018). Here we hypothesized that house dust mite (HDM) will skew bronchial epithelial cells (BECs) to go into necroptosis instead of apoptosis during viral stimuli. Methods: Primary BECs from asthmatic donors were pre-exposed with HDM (20µg/mL) for 24 hours then stimulated with the viral mimic dsRNA (10µg/mL) for 24 hours. Samples were analyzed with RT-qPCR for IFN-s and western blot for the apoptotic marker cleaved caspase-3 and the necroptosis marker phosphorylated MLKL. Results: dsRNA stimulation alone increased IFN-s gene expression and were followed by increased protein levels of the apoptotic marker cleaved caspsase-3 and necroptosis marker phosphorylated MLKL compared to control. Pre-exposure with HDM decreased dsRNA induced IFN-s gene expression and protein expression of cleaved caspase-3. However, dsRNA induced protein expression of phosphorylated MLKL was not affected by pre-exposure with HDM. Conclusion: HDM exposure prior to dsRNA stimulation reduced the expression of the apoptotic marker caspase-3 but not the necroptosis marker phosphorylated MLKL in BECs obtained from asthmatic donors. Our data suggest that HDM skews towards potential pathogenic epithelial cell death (necroptosis) during viral infection which could further aggravate inflammation at asthma exacerbation.