Allergens stimulate store-operated calcium entry and cytokine production in airway epithelial cells

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.

Tight junctions in pulmonary epithelia during lung inflammation

“…Bacterial and viral infections induce TNF-α, IL-1α, IL-1β, IL-6, IL-8 and IL-18 [21, 77, 101, 115, 143]. In addition, allergic agents such like cationic peptides [21], proteolytic active [12, 29, 58, 59, 68, 117] as well as non-proteolytic allergens [98] induce the release of IL-6, IL-8, granulocyte macrophage colony-stimulating factor (GM-CSF) and monocyte chemotractant protein 1 (MCP-1). The response to proteolytically active allergens involves store-operated Ca 2+ entry in epithelial cells [58, 59], and it should be noted that bacterial exotoxins also activate store-operated Ca 2+ entry [128].…”

“…In addition, allergic agents such like cationic peptides [21], proteolytic active [12, 29, 58, 59, 68, 117] as well as non-proteolytic allergens [98] induce the release of IL-6, IL-8, granulocyte macrophage colony-stimulating factor (GM-CSF) and monocyte chemotractant protein 1 (MCP-1). The response to proteolytically active allergens involves store-operated Ca 2+ entry in epithelial cells [58, 59], and it should be noted that bacterial exotoxins also activate store-operated Ca 2+ entry [128]. Other factors, which belong to danger-associated molecular patterns (DAMP), like adenosine [117], prostaglandin [20] or histamine [120], initiate IL-1β, IL-6, IL-8 and GM-CSF production and release.…”

“…The recruitment of neutrophils is driven via direct perturbation of epithelial cells. Airborne insults such like cigarette smoke, diesel dusts, bacterial infection and allergens induce the release of chemokines IL6, IL8, TNF, IL-1, GM-SCF, MCP-1 from airway epithelial cells [12, 20, 21, 29, 47, 58, 59, 68, 77, 98, 101, 115, 117, 119, 120, 143]. Release of these cytokines either recruit neutrophils directly [140] or induce IL-17 release from T H 17 cells [137].…”

Protease‐activated receptor 2 activates CRAC‐mediated Ca 2+ influx to cause prostate smooth muscle contraction

“…PAR2 is known to mediate contraction of gastric smooth muscles through a PLCβ‐mediated signaling pathway that involves Ca 2+ flux . PAR2 activation has been shown to elevate Ca 2+ in many cell types . However, it is not known if PAR2 mediates Ca 2+ flux in smooth muscles of the prostate.…”

“…Scale bar represents 50 µm elevate Ca 2+ in many cell types. [18][19][20] However, it is not known if PAR2 mediates Ca 2+ flux in smooth muscles of the prostate. We hypothesized that PAR2 may cause PSMC contraction through PLCβ and subsequent Ca 2+ flux.…”