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Involvement of purinergic receptors and NOD‐like receptor‐family protein 3‐inflammasome pathway in the adenosine triphosphate‐induced cytokine release from macrophages

Adenosine triphosphate (ATP) has been described as a danger signal activating the NOD‐like receptor‐family protein 3 (NLRP3)‐inflammasome leading to the pro‐inflammatory cytokine, interleukin (IL)‐1β, release in the lung. The NLRP3‐inflammasome pathway has been previously described to be involved in experimental collagen deposition and the development of pulmonary fibrosis. The aim of the present study was to investigate the role of the NLRP3 inflammasome pathway and P2X7 purinergic receptor in the activation of human macrophages in vitro by ATP. We showed that adenosine 5′‐[γ‐thio]triphosphate tetralithium salt (ATPγS) and 2′,3′‐O‐(4‐benzoylbenzoyl) adenosine 5′‐triphosphate (BzATP), two stable analogs of ATP, are able to potentiate the release of IL‐1β from human monocyte‐derived macrophages induced by low concentration of lipopolysaccharide (LPS). However, in the same conditions no increase in IL‐1α and IL‐6 was observed. Immunochemistry has shown that human macrophages natively express NLRP3 and purinergic P2X7 receptors (P2X7R). NLRP3 and IL‐1β mRNA expression were induced from LPS‐primed macrophages, but also after 5‐h treatment of BzATP as analysed by reverse transcription quantitative polymerase chain reaction. However, other inflammasome pathways (NLRP1, NLRP2, NLRC4, NLRP6 and AIM2) and P2X7R were not induced by BzATP. We observed that P2X7R antagonists, A‐438079 and A‐740003, were able to reduce the release of IL‐1β, but not of IL‐1α and IL‐6 from macrophages stimulated by ATPγS or BzATP. The present results showed the involvement of the P2X7R‐NLRP3 inflammasome pathway in the secretion of IL‐1β from ATP‐stimulated human macrophages, and suggest that P2X7R were not involved in IL‐1α and IL‐6 release. This study also points out that repression of the P2X7R represents a novel potential therapeutic approach to control fibrosis in lung injury.