Adenosine metabolized from extracellular ATP promotes type 2 immunity through triggering A2BAR signaling in intestinal epithelial cells

El-Naccache, Darine W.; Chen, Fei; Palma, Mark; Lemenze, Alexander; Fischer, Matthew A.; Wu, Wenhui; Mishra, Pankaj Kumar; Eltzschig, Holger K.; Robson, Simon C.; Virgilio, Francesco Di; Yap, George; Edelblum, Karen L.; Haskó, György; Gause, William C.

doi:10.1016/j.celrep.2022.111150

Cited by 15 publications

(9 citation statements)

References 77 publications

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“…14,15 In contrast to the current mainstream food allergy animal models that involve only a few intragastric challenges over a short period, [39][40][41] we postulate that continuous intake of high doses of allergens may create an inflammatory microenvironment that facilitates the release and detection of eATP. 17,21,42 Following this, we demonstrated a significant increase in ileal luminal eATP concentration in mice fed with an EW diet.…”

Section: Discussionmentioning

confidence: 60%

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Extracellular adenosine triphosphate skews the T helper cell balance and enhances neutrophil activation in mice with food allergies

Zhang,

Chen,

Yang

et al. 2024

Food Funct.

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Section: Discussionmentioning

confidence: 60%

“…20 Existing evidence suggests that the accumulation of luminal eATP worsens pathologic lesions. [21][22][23][24] Indeed, during the food challenge period, the introduction of ATPγs led to sharp weight loss, lower core temperature, and severer food avoidance (Fig. 2B and C and Fig.…”

Section: Atp Analog Treatment Worsened the Allergic Symptomsmentioning

confidence: 96%

Extracellular adenosine triphosphate skews the T helper cell balance and enhances neutrophil activation in mice with food allergies

Zhang,

Chen,

Yang

et al. 2024

Food Funct.

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“…Necrotic cardiomyocytes in the infarct area provide a major stimulus for the post-infarction inflammatory response by releasing danger-associated molecular patterns (DAMPs) 36 . DAMPs binding to pattern recognition receptors (PRRs) induce inflammatory pathways and stimulate cytokine secretion 37 . Surviving cardiomyocytes in the peri-infarct zone adjoining the necrotic core are strategically positioned to signal to immune cells, vascular, and other interstitial cells that migrate to the region 38 .…”

Section: Discussionmentioning

confidence: 99%

Targeting WWP1 ameliorates cardiac ischemic injury by suppressing KLF15-ubiquitination mediated myocardial inflammation

Lu¹,

Yang²,

Qi³

et al. 2023

Theranostics

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Rationale: Previous studies have suggested that myocardial inflammation plays a critical role after ischemic myocardial infarction (MI); however, the underlying mechanisms still need to be fully elucidated. WW domain-containing ubiquitin E3 ligase 1 (WWP1) is considered as an important therapeutic target for cardiovascular diseases due to its crucial function in non-ischemic cardiomyopathy, though it remains unknown whether targeting WWP1 can alleviate myocardial inflammation and ischemic injury post-MI. Methods: Recombinant adeno-associated virus 9 (rAAV9)-cTnT-mediated WWP1 or Kruppel-like factor 15 (KLF15) gene transfer and a natural WWP1 inhibitor Indole-3-carbinol (I3C) were used to determine the WWP1 function in cardiomyocytes. Cardiac function, tissue injury, myocardial inflammation, and signaling changes in the left ventricular tissues were analyzed after MI. The mechanisms underlying WWP1 regulation of cardiomyocyte phenotypes in vitro were determined using the adenovirus system. Results: We found that WWP1 expression was up-regulated in cardiomyocytes located in the infarct border at the early phase of MI and in hypoxia-treated neonatal rat cardiac myocytes (NRCMs). Cardiomyocyte-specific WWP1 overexpression augmented cardiomyocyte apoptosis, increased infarct size and deteriorated cardiac function. In contrast, inhibition of WWP1 in cardiomyocytes mitigated MI-induced cardiac ischemic injury. Mechanistically, WWP1 triggered excessive cardiomyocyte inflammation after MI by targeting KLF15 to catalyze K48-linked polyubiquitination and degradation. Ultimately, WWP1-mediated degradation of KLF15 contributed to the up-regulation of p65 acetylation, and activated the inflammatory signaling of MAPK in ischemic myocardium and hypoxia-treated cardiomyocytes. Thus, targeting of WWP1 by I3C protected against cardiac dysfunction and remodeling after MI. Conclusions: Our study provides new insights into the previously unrecognized role of WWP1 in cardiomyocyte inflammation and progression of ischemic injury induced by MI. Our findings afford new therapeutic options for patients with ischemic cardiomyopathy.

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“…Moreover, this immune regulation can facilitate the extravasation of the eggs through the intestinal wall and be expelled in the faeces 60 . Furthermore, the role of adenosine in granuloma formation and modulation of the immune response in experimental model in helminth infections caused by Heligmosomoides polygyrus bakeri (Hpb) has recently been demonstrated 61 …”

Section: Discussionmentioning

confidence: 99%

“…60 Furthermore, the role of adenosine in granuloma formation and modulation of the immune response in experimental model in helminth infections caused by Heligmosomoides polygyrus bakeri (Hpb) has recently been demonstrated. 61 We hypothesize that the action of SmATPDase 1 and 2 individually generates a smaller amount of the AMP substrate that will be converted into adenosine through the action of the SmAP, SmNPP-5, and ecto-5 0 -nucleotidase enzymes. This smaller amount of adenosine generated will act preferentially on pro-inflammatory receptors (A1 and A3) on the surface of immune cells, leading to the assembly of a mixed response profile characterized by the presence of Th1 (IFN-gamma, TNF, IL-6 and IL-2) and Th2 (IL-4 and IL-13) cytokines.…”

Section: Expression Of Smatpdases Contributes To the Positive Associa...mentioning

confidence: 99%

Expression of SmATPDases 1 and 2 in Schistosoma mansoni eggs favours IL‐10 production in infected individuals

Gomides,

de Souza,

de Figueiredo

et al. 2023

Parasite Immunology

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A role of IL‐10 is down‐regulating T‐cell responses to schistosome antigens. Since SmATPDases can be correlated to modulation of the immune response, we evaluated the expression of enzymes in S. mansoni eggs. Faecal samples were collected from 40 infected individuals to detect coding regions of the SmATPDases. The cytokines were measured in supernatants of PBMC. The analysis was performed by the global median determination and set up high producers (HP) of cytokines. Six individuals expressed SmATPDase1, six expressed SmATPDase2 and six expressed both enzymes. The group who expressed only SmATPDase1 showed a high frequency of IFN‐γ, TNF IL‐4 HP; individuals who expressed only SmATPDase2 showed a high frequency of IFN‐γ, IL‐6 and IL‐4 HP; and individuals who expressed both enzymes showed a high frequency of IL‐10 HP. The comparison of the IFN‐γ/IL‐10 ratio presented higher indices in the group who had SmATPDase 2 expression than those who had the expression of both enzymes. The positive correlation between infection intensity and IL‐10 levels remained only in the positive SmATPDase group. The IL‐10 is the only cytokine induced by the expression of both enzymes. Our data suggest that the expression of both enzymes seems to be a factor that modulates the host immune response by inducing high IL‐10 production.

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Adenosine metabolized from extracellular ATP promotes type 2 immunity through triggering A2BAR signaling in intestinal epithelial cells

Cited by 15 publications

References 77 publications

Extracellular adenosine triphosphate skews the T helper cell balance and enhances neutrophil activation in mice with food allergies

Extracellular adenosine triphosphate skews the T helper cell balance and enhances neutrophil activation in mice with food allergies

Targeting WWP1 ameliorates cardiac ischemic injury by suppressing KLF15-ubiquitination mediated myocardial inflammation

Expression of SmATPDases 1 and 2 in Schistosoma mansoni eggs favours IL‐10 production in infected individuals

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