Allergens produce serine proteases‐dependent distinct release of metabolite <scp>DAMP</scp>s in human bronchial epithelial cells

Ramu, Sangeetha; Menzel, Mandy; Bjermer, Leif; Andersson, Cecilia; Akbarshahi, Hamid; Uller, Lena

doi:10.1111/cea.13071

Cited by 25 publications

(37 citation statements)

References 48 publications

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“…These data support previous findings of papain-related protection against S. mansoni in CD-1 mice [7], [18] and against S. haematobium in hamsters [15]. Exposure to enzymatically active cysteine peptidases consistently induces epithelial barrier disruption, with subsequent conversion of dying cell-derived purines into uric acid, a major amplifier of type 2 immune responses [19], [35], [36], [37], [38], [39], [40] and modulator of lipid metabolism, especially lipid metabolism involving ARA, which is needed for cell membrane synthesis and repair [20], [22], [41]. In support of this hypothesis, papain injection skewed innate and acquired immune responses to the antigens of invading S. mansoni towards the type 2 axis, preceding the effects of egg-derived soluble antigens, with preponderance of IgG1 antibodies and accumulation of uric acid and ARA in the lung 7 days PI and in the liver starting 17 days PI.…”

Section: Discussionsupporting

confidence: 89%

Role of T lymphocytes and papain enzymatic activity in the protection induced by the cysteine protease against Schistosoma mansoni in mice

Tallima

Dahab

Ridi

2019

Journal of Advanced Research

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Section: Discussionsupporting

confidence: 89%

Role of T lymphocytes and papain enzymatic activity in the protection induced by the cysteine protease against Schistosoma mansoni in mice

Tallima

Dahab

Ridi

2019

Journal of Advanced Research

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“…However, a close examination of the Ca 2ϩ experiments shows a secondary Ca 2ϩ signal invoked by the Alternaria filtrate that is absent in the AASP experiments. It has been shown that Alternaria exposure of epithelial cells can induce metabolite release, including ATP (41,54,58), and such metabolites could extend the Ca 2ϩ signal. However, the Ca 2ϩ signal induced by AASP was more similar to what is typically seen by specific PAR 2 -activating peptides (19).…”

Section: Discussionmentioning

confidence: 99%

Protease-activated receptor-2 signaling through β-arrestin-2 mediates Alternaria alkaline serine protease-induced airway inflammation

Yee

Nichols

Polley

et al. 2018

American Journal of Physiology-Lung Cellular and Molecular Phys

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Alternaria alternata is a fungal allergen associated with severe asthma and asthma exacerbations. Similarly to other asthma-associated allergens, Alternaria secretes a serine-like trypsin protease(s) that is thought to act through the G protein-coupled receptor protease-activated receptor-2 (PAR2) to induce asthma symptoms. However, specific mechanisms underlying Alternaria-induced PAR2 activation and signaling remain ill-defined. We sought to determine whether Alternaria-induced PAR2 signaling contributed to asthma symptoms via a PAR2/β-arrestin signaling axis, identify the protease activity responsible for PAR2 signaling, and determine whether protease activity was sufficient for Alternaria-induced asthma symptoms in animal models. We initially used in vitro models to demonstrate Alternaria-induced PAR2/β-arrestin-2 signaling. Alternaria filtrates were then used to sensitize and challenge wild-type, PAR2−/− and β-arrestin-2−/− mice in vivo. Intranasal administration of Alternaria filtrate resulted in a protease-dependent increase of airway inflammation and mucin production in wild-type but not PAR2−/− or β-arrestin-2−/− mice. Protease was isolated from Alternaria preparations, and select in vitro and in vivo experiments were repeated to evaluate sufficiency of the isolated Alternaria protease to induce asthma phenotype. Administration of a single isolated serine protease from Alternaria, Alternaria alkaline serine protease (AASP), was sufficient to fully activate PAR2 signaling and induce β-arrestin-2−/−-dependent eosinophil and lymphocyte recruitment in vivo. In conclusion, Alternaria filtrates induce airway inflammation and mucus hyperplasia largely via AASP using the PAR2/β-arrestin signaling axis. Thus, β-arrestin-biased PAR2 antagonists represent novel therapeutic targets for treating aeroallergen-induced asthma.

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“…Several common airborne aeroallergens have been reported to trigger the calcium-dependent exocytosis of ATP from human airway EpCs (63,64). To determine whether aeroallergens trigger BrC CysLT generation and whether it may be mediated by P2Y2, we incubated BrCs ex vivo with increasing doses of the mold aeroallergen Alternaria or the house dust mite aeroallergen Dermatophagoides pteronyssinus (Dp).…”

Section: Aeroallergens Elicit P2y2-dependent Brc Cyslt Generation Andmentioning

confidence: 99%

Airway brush cells generate cysteinyl leukotrienes through the ATP sensor P2Y2

et al. 2020

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Chemosensory epithelial cells (EpCs) are specialized cells that promote innate type 2 immunity and protective neurally mediated reflexes in the airway. Their effector programs and modes of activation are not fully understood. Here, we define the transcriptional signature of two choline acetyltransferase–expressing nasal EpC populations. They are found in the respiratory and olfactory mucosa and express key chemosensory cell genes including the transcription factor Pou2f3, the cation channel Trpm5, and the cytokine Il25. Moreover, these cells share a core transcriptional signature with chemosensory cells from intestine, trachea and thymus, and cluster with tracheal brush cells (BrCs) independently from other respiratory EpCs, indicating that they are part of the brush/tuft cell family. Both nasal BrC subsets express high levels of transcripts encoding cysteinyl leukotriene (CysLT) biosynthetic enzymes. In response to ionophore, unfractionated nasal BrCs generate CysLTs at levels exceeding that of the adjacent hematopoietic cells isolated from naïve mucosa. Among activating receptors, BrCs express the purinergic receptor P2Y2. Accordingly, the epithelial stress signal ATP and aeroallergens that elicit ATP release trigger BrC CysLT generation, which is mediated by the P2Y2 receptor. ATP- and aeroallergen-elicited CysLT generation in the nasal lavage is reduced in mice lacking Pou2f3, a requisite transcription factor for BrC development. Last, aeroallergen-induced airway eosinophilia is reduced in BrC-deficient mice. These results identify a previously undescribed BrC sensor and effector pathway leading to generation of lipid mediators in response to luminal signals. Further, they suggest that BrC sensing of local damage may provide an important sentinel immune function.

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Allergens produce serine proteases‐dependent distinct release of metabolite DAMPs in human bronchial epithelial cells

Cited by 25 publications

References 48 publications

Role of T lymphocytes and papain enzymatic activity in the protection induced by the cysteine protease against Schistosoma mansoni in mice

Role of T lymphocytes and papain enzymatic activity in the protection induced by the cysteine protease against Schistosoma mansoni in mice

Protease-activated receptor-2 signaling through β-arrestin-2 mediates Alternaria alkaline serine protease-induced airway inflammation

Airway brush cells generate cysteinyl leukotrienes through the ATP sensor P2Y2

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