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

Dai, Xiuju; Tohyama, Mikiko; Murakami, Masamoto; Shiraishi, Ken; Liu, Shuang; Mori, Hideki; Utsunomiya, Ryo; Maeyama, Kazutaka; Sayama, Koji

doi:10.1016/j.bbadis.2020.165719

Cited by 38 publications

(44 citation statements)

References 58 publications

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“…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.…”

Section: Discussionsupporting

confidence: 91%

“…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].…”

Section: Discussionmentioning

confidence: 98%

“…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].…”

Section: Introductionmentioning

confidence: 99%

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

Liu¹,

Zhou²,

Feng³

et al. 2021

Preprint

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BackgroundAllergic rhinitis (AR) is an inflammatory disease of the nasal mucosa, which is triggered by stimulations of environmental allergens such as house dust mite (HDM). Th2-type proinflammatory factor interleukin 33 (IL-33) plays an important role in the pathogenesis of AR, but it remains unknown how IL-33 products in human nasal epithelial cells (HNECs) mediated by HDM. MethodsWe investigated the effect of HDM allergens by analyzing the accumulation of Ca2+ levels and IL-33 release in HNECs. Involvements of Adenosine triphosphate (ATP)-dependent activation of P2Y-PLC-IP3 pathways, downstream of Ca2+ signaling and P38/ERK pathways were studied, using the P2Y-PLC-IP3 pathways agonists, the calcium chelators, and P38/ERK pathways inhibitors. ResultsDer p induced expression of IL-33 mRNA and protein in HNECs via ERK/P38 pathways. Average 69.4% of co-localization of quinacrine and Lyso-tracker fluorescent puncta revealed that ATP was mainly stored in the lysosomes of nasal epithelial cells. After stimulation with Der p, ATP released from lysosomes by P2Y-PLC-IP3-Ca2+pathways. The ATP assay of HNECs culture supernatants implied an acute accumulation of extracellular ATP immediately after the Der p stimulation. Using P2Y-PLC-IP3 signaling inhibitors, we found that the Der p-induced IL-33 release was dependent on ATP-P2Y-PLC-IP3 signaling, followed by abolishing the ERK/P38 pathways. ConclusionDer p induced an acute accumulation of extracellular ATP which activated PY2-PLC-IP3 pathways to induce Ca2+ releasing from endoplasmic reticulum (ER), and intracellular Ca2+ induced ATP release from lysosomes from HNECs. ATP activated PY2-PLC-IP3 pathways followed by transactivation of ERK/P38 pathways which induced the expression of IL-33 mRNA and protein.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

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

Liu¹,

Zhou²,

Feng³

et al. 2021

Preprint

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“…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 .…”

Section: Introductionmentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

Allergen protease-induced Gsdmd p40 controls IL-33 secretion

Sun

et al. 2021

Preprint

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Interleukin (IL)-33, an epithelial cell-derived cytokine that responds rapidly to environmental insult, has a critical role in initiating airway inflammation, such as that in asthma. However, the molecular mechanism underlying IL-33 secretion following allergen exposure is not clear. Here, we demonstrated that Gasdermin D (Gsdmd) functions as a conduit for IL-33 secretion following allergen protease exposure. Gsdmd was rapidly cleaved into a functional neo-form, the N-terminal p40 fragment (p40 NT-Gsdmd), in the murine airway epithelium when cells were exposed to allergen proteases from fungi, house dust mites (HDMs), or bacteria. This cleavage event that produces the p40 Gsdmd fragment was independent of inflammatory caspases-1/11, as it could not be inhibited by caspase-1 and caspase-11 deficiency in murine cells. The functional p40 NT-Gsdmd fragment directly contributed to the secretion of both the nuclear full-length form and cytosolic mature form of IL-33. Both Gsdmd deficiency and blockade of the generation of p40 by amino acid mutation or deletion of residues 308–313 (ELRQQ) in the Gsdmd sequence could efficiently prevent IL-33 release in airway epithelial cells. In mice, Gsdmd deficiency prevented IL-33 release and hindered the activation of group 2 innate lymphoid cells (ILC2s), thus alleviating airway inflammation and lung tissue damage after stimulation with HDMs or papain. Our findings uncovered a mechanism of Gsdmd-mediated IL-33 release under allergen exposure and offer insight into Gsdmd cleavage prevention as a potential approach to reduce allergic airway inflammation.

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EGFR ligands synergistically increase IL‐17A‐induced expression of psoriasis signature genes in human keratinocytes via IκBζ and Bcl3

et al. 2022

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Various epidermal growth factor receptor (EGFR) ligands are highly expressed in the epidermis of psoriasis lesions, and abnormal EGFR activation appears to be involved in the pathogenesis of psoriasis. However, how EGFR signaling contributes to the development of psoriasis is unclear. Interleukin (IL)‐17A, a critical effector of the IL‐23/IL‐17A pathway, increases the expression of psoriasis signature genes in keratinocytes and plays an essential role in the pathogenesis of psoriasis by inducing IκBζ, a critical transcriptional regulator in psoriasis. In this study, we stimulated primary human keratinocytes with IL‐17A and various EGFR ligands to investigate whether EGFR ligands regulate the expression of psoriasis signature genes. In cultured normal human keratinocytes and a living skin equivalent, EGFR ligands did not induce psoriasis‐related gene expression, but significantly enhanced the IL‐17A‐mediated induction of various psoriasis signature genes, including antimicrobial peptides, cytokines, and chemokines. This was dependent on an EGFR activation‐mediated synergistic increase in IL‐17A‐induced IκBζ expression and was partially mediated by the EGFR‐dependent upregulation of Bcl3. Therefore, EGFR ligands can act as synergistic agents of IL‐17A signaling by stimulating the epidermal production of psoriasis signature genes in psoriasis lesions. This study reveals a potential mechanism by which EGFR signaling contributes to the pathogenesis of psoriasis.

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

Cited by 38 publications

References 58 publications

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

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

Allergen protease-induced Gsdmd p40 controls IL-33 secretion

EGFR ligands synergistically increase IL‐17A‐induced expression of psoriasis signature genes in human keratinocytes via IκBζ and Bcl3

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