House dust mite allergens induce interleukin 33 (IL-33) synthesis and release from keratinocytes via ATP-mediated extracellular signaling

House Dust Mite Induces IL-33 Release From Human Nasal Epithelial Cells via P2Y Purinergic Signals and ERK/P38 MAPK Pathways.

“…ATP is reported to evoke ER Ca 2+ release via P2Y-PLC-IP3 pathway and P2X ion channels in marginal cells, human monocytes and macrophage [18,32] In our study, pre-incubation with apyrase which hydrolyzed ATP into ADP e ciently suppressed HDM induced Ca 2+ responses. These results were consistent with those found in human keratinocytes which con rmed HDM induced acute extracellular accumulation of ATP activating P2Y 2 receptors [19]. Then, we found HDM-induced intracellular Ca 2+ responses were partially inhibited by P2Y-PLC-IP3 pathway inhibitors and ER inhibitor TG, thereby con rming that P2X ion channels were also involved in HMDinduced Ca 2+ release and ER was not the only source of intracellular Ca 2+ store.…”

“…IL-33 expression is signi cantly higher in nasal mucosa epithelial cells of AR patients and AR rats than it in the control groups, which can induce the production of Th2 in ammatory cytokines via binding to ST2 [23,24]. HDM, as the main allergen of perennial AR, is reported to induce IL-33 release from keratinocytes [19], pulmonary epithelial cells [25] and bone marrow [26]. Our ndings are consistent with those reports that HDM (Der p) induces IL-33 protein(30Kda) to be released from nuclei to cytoplasm and then to extracellular space of human nasal epithelial cells (Figure .1).HDM is reported to stimulate airway smooth muscle cells through TLRs and NLRs signaling pathways to trigger MyD88 signaling pathway, which further activates NF-κB and MAPK pathways, thereby inducing cells to release IL-33 [9].…”

“…Our teams' previous studies have con rmed that ATP induces the release of Ca 2+ from the endoplasmic reticulum (ER) calcium store of the marginal cells through the P2Y2-PLC-IP3 signaling pathway, and ATP releases from lysosomes through exocytosis [18]. In keratinocytes, when stimulated by HDM, the cells quickly release a large amount of ATP, which rapidly induces the release of Ca2 + from the endoplasmic reticulum via activating extracellular P2Y purinergic receptor signaling, and enables activated keratinocytes to release IL-33 [19]. HDM has also been con rmed to induce keratinocytes to release IL-1β through the ERK and P38 MAPK pathways, thereby inducing allergic dermatitis [20].…”

Allergen protease-induced Gsdmd p40 controls IL-33 secretion

“…These allergens are often composed of various components, such as enzymes and complex polysaccharides. Certain enzymatically active components derived from allergens, including Der p and Der f from HDMs 4,5 , Asp f from Aspergillus oryzae 6 , the Subtilisin protease from Bacillus species 7 and Per a from cockroaches 8,9 , have been reported to have the ability to induce IL-33 release and promote allergic-type 2 airway in ammation in vivo. Allergen proteases induce an allergic in ammatory response through mechanisms that involve directly damaging epithelial cell tight junctions 10,11,12,13 , acting on protease-activated receptors (Par2) or activating the pattern recognition receptor Toll-like receptor 4 (TLR4) on multiple cell lineages, including airway epithelial cells, macrophages and basophils 10,14,15 .…”

“…Some researchers discovered that in living cells, nuclear IL-33 can also be secreted in response to nonlethal mechanical stress 36,37 . Other stimuli, such as cockroaches, uric acid, exogenous ATP, HDMs, and Alternaria allergens, have also been reported to induce IL-33 release from epithelial cell lineages without obvious cell death 4,16,17,18,38,39,40,41 . Recently, serum amyloid A was de ned as a soluble pattern recognition receptor for allergenic mite FABPs that drive the epithelial release of IL-33 42 ; however, whether it participates in the recognition of other allergenic stimuli still needs to be determined.…”