Abstract
Aberrant immune responses to environmental allergens including insect allergens from house dust mites and cockroaches contribute to allergic inflammatory diseases such as asthma in susceptible individuals. Airway epithelial cells (AECs) play a critical role in this process by sensing the proteolytic activity of allergens via protease-activated receptors (PAR2) to initiate inflammatory and immune responses in the airway. Elevation of cytosolic Ca2+ is an important signaling event in this process, yet the fundamental mechanism by which allergens induce Ca2+ elevations in AECs remains poorly understood. Here we find that extracts from dust mite and cockroach induce sustained Ca2+ elevations in AECs through the activation of Ca2+ release-activated Ca2+ (CRAC) channels encoded by Orai1 and STIM1. CRAC channel activation occurs, at least in part, through allergen mediated stimulation of PAR2 receptors. The ensuing Ca2+ entry then activates NFAT/calcineurin signaling to induce transcriptional production of the proinflammatory cytokines IL-6 and IL-8. These findings highlight a key role for CRAC channels as regulators of allergen induced inflammatory responses in the airway.
Highlights
Signals in response to allergens is needed to better understand how cytokine signaling pathways are induced in AECs and to translate this knowledge in the quest for identifying novel targets for therapy
We and others have previously shown that store-operated calcium entry (SOCE) is a major mechanism of Ca2+ influx in bronchial epithelial cells and is stimulated by activation of protease activated receptor type 2 (PAR2) receptors[15,16]
Knockdown of the Ca2+ release-activated Ca2+ (CRAC) channel proteins STIM1 and Orai[1] significantly abrogated the average sustained Ca2+ signals seen in response to HDM (Fig. 3D–F). These results indicate that HDM allergens mobilize cellular Ca2+ elevations in bronchial epithelial cells by depleting ER Ca2+ stores and activating CRAC channels encoded by STIM1 and Orai[1]
Summary
Signals in response to allergens is needed to better understand how cytokine signaling pathways are induced in AECs and to translate this knowledge in the quest for identifying novel targets for therapy. We and others have shown that CRAC channels are a major mechanism for eliciting Ca2+ signals in AECs and are activated in response to PAR2 stimulation[15,16]. Given that many inhaled allergens produce Ca2+ elevations in AECs and are thought to mediate their inflammatory effects, at least in part, by stimulating PAR2 receptors[9,11,12,13], we sought to investigate whether CRAC channels contribute to the downstream response to allergens in bronchial BEAS-2B cells[9,11,12,13]. The ensuing Ca2+ signal induces the generation of IL-6 and IL-8
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