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Regulation of inflammatory response by extracellular ATP and P2X7 receptor signalling: through and beyond the inflammasome

Objective

Inflammatory diseases affect over 80 million people worldwide and accompany many diseases of industrialized countries, being the majority of them infection-free conditions. There are few efficient anti-inflammatory drugs to treat chronic inflammation and thus, there is an urgent need to validate novel targets. We now know that innate immunity is the main coordinator and driver of inflammation. Recently, we and others have shown that the activation of purinergic P2X7 receptors (P2X7R) in immune cells is a novel and increasingly validated pathway to initiate inflammation through the activation of the NLRP3 inflammasome and the release of IL-1β and IL-18 cytokines. However, how NLRP3 sense P2X7R activation is not fully understood. Furthermore, extracellular ATP, the physiological P2X7R agonist, is a crucial danger signal released by injured cells, and one of the most important mediators of infection-free inflammation. We have also identified novel signalling roles for P2X7R independent on the NLRP3 inflammasome, including the release of proteases or inflammatory lipids. Therefore, P2X7R has generated increasing interest as a therapeutic target in inflammatory diseases, being drug like P2X7R antagonist in clinical trials to treat inflammatory diseases. However, it is often questioned the functionality of P2X7R in vivo, where it is thought that extracellular ATP levels are below the threshold to activate P2X7R. The overall significance of this proposal relays to elucidate how extracellular ATP controls host-defence in vivo, ultimately depicting P2X7R signalling through and beyond inflammasome activation. We foresee that our results will generate a leading innovative knowledge about in vivo extracellular ATP signalling during the host response to infection and sterile danger.

Field of science

  • /natural sciences/biological sciences/biochemistry/biomolecules/lipids
  • /medical and health sciences/health sciences/inflammatory diseases

Call for proposal

ERC-2013-CoG
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Funding Scheme

ERC-CG - ERC Consolidator Grants

Host institution

FUNDACION PARA LA FORMACION E INVESTIGACION SANITARIAS DE LA REGION DE MURCIA
Address
Calle Luis Fontes Pagan 9 Edif Emi Hospital Reina Sofia
30003 Murcia
Spain
Activity type
Research Organisations
EU contribution
€ 1 794 948
Principal investigator
Pablo Pelegrin Vivancos (Dr.)
Administrative Contact
Juan Pedro Serna Marmol (Mr.)

Beneficiaries (1)

FUNDACION PARA LA FORMACION E INVESTIGACION SANITARIAS DE LA REGION DE MURCIA
Spain
EU contribution
€ 1 794 948
Address
Calle Luis Fontes Pagan 9 Edif Emi Hospital Reina Sofia
30003 Murcia
Activity type
Research Organisations
Principal investigator
Pablo Pelegrin Vivancos (Dr.)
Administrative Contact
Juan Pedro Serna Marmol (Mr.)