2. Academic Validation
  3. Stimulation of P2Y11 receptor modulates cardiac fibroblasts secretome toward immunomodulatory and protective roles after Hypoxia/Reoxygenation injury

Stimulation of P2Y11 receptor modulates cardiac fibroblasts secretome toward immunomodulatory and protective roles after Hypoxia/Reoxygenation injury

  • J Mol Cell Cardiol. 2018 Aug:121:212-222. doi: 10.1016/j.yjmcc.2018.07.245.
Claudie Lefort 1,  Lauriane Benoist 1,  Stéphanie Chadet 1,  Marie Piollet 1,  Audrey Heraud 1,  Dominique Babuty 2,  Christophe Baron 3,  Fabrice Ivanes 4,  Denis Angoulvant 2
Affiliations

Affiliations

  • 1 EA 4245 "Transplantation, Immunologie et Inflammation", Loire Valley Cardiovascular Collaboration & Université de Tours, 10 Boulevard Tonnellé, 37032 Tours, France.
  • 2 EA 4245 "Transplantation, Immunologie et Inflammation", Loire Valley Cardiovascular Collaboration & Université de Tours, 10 Boulevard Tonnellé, 37032 Tours, France; Service de Cardiologie, Centre Hospitalier Régional Universitaire de Tours, 37044 Tours, France.
  • 3 EA 4245 "Transplantation, Immunologie et Inflammation", Loire Valley Cardiovascular Collaboration & Université de Tours, 10 Boulevard Tonnellé, 37032 Tours, France; Service de Néphrologie et d'Immunologie Clinique, Centre Hospitalier Régional Universitaire de Tours, 37044 Tours, France.
  • 4 EA 4245 "Transplantation, Immunologie et Inflammation", Loire Valley Cardiovascular Collaboration & Université de Tours, 10 Boulevard Tonnellé, 37032 Tours, France; Service de Cardiologie, Centre Hospitalier Régional Universitaire de Tours, 37044 Tours, France. Electronic address: [email protected].
PMID: 30031814 DOI: 10.1016/j.yjmcc.2018.07.245
Abstract

Cardiac fibroblasts are important regulators of myocardial structure and function. Their implications in pathological processes such as Ischemia/Reperfusion are well characterized. Cardiac fibroblasts respond to stress by excessive proliferation and secretion of pro-inflammatory cytokines and Other factors, e.g. ATP, leading to purinergic receptors activation. P2Y11 receptor (P2Y11R) is an ATP-sensitive GPCR playing an immunomodulatory role in human dendritic cells (DC). We hypothesized that P2Y11R stimulation modulated the pro-inflammatory responses of human cardiac fibroblasts (HCF) to Hypoxia/Reoxygenation (H/R) mainly by acting on their secretome. P2Y11R stimulation in HCF at the onset of reoxygenation significantly limited H/R-induced proliferation (-19%) and pro-inflammatory cytokines and ATP secretion (-44% and -83% respectively). Exposure of DC to HCF secretome increased their expression of CD83, CD25 and CD86, suggesting a switch from immature to mature phenotype. Under LPS stimulation, DC had a pro-inflammatory profile (high IL-12/IL-10 ratio) that was decreased by HCF secretome (-3,8-fold), indicating induction of a tolerogenic profile. Moreover, P2Y11R inhibition in HCF led to high IL-12 secretion in DC, suggesting that the immunomodulatory effect of HCF secretome is P2Y11R-dependant. HCF secretome reduced H/R-induced cardiomyocytes death (-23%) through RISK pathway activation. P2Y11R inhibition in HCF induced a complete loss of HCF secretome protective effect, highlighting the cardioprotective role of P2Y11R. Our data demonstrated paracrine interactions between HCF, cardiomyocytes and DC following H/R, suggesting a key role of HCF in the cellular responses to reperfusion. These results also demonstrated a beneficial role of P2Y11R in HCF during H/R and strongly support the hypothesis that P2Y11R is a modulator of I/R injury.

Keywords

Cardiac fibroblast; Cardioprotection; Immunomodulation; Ischemia reperfusion injury; P2Y purinoceptor.

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