The Danger Theory developed by Polly Matzinger specifies that what really matters for the immune system is not to distinguish between self « to protect » and non-self « to fight ». Any potentially detrimental situation for the host would be able to generate endogenous danger signal that are able to mount an immune response to eventually return to baseline. Lung repeated expositions to toxic environnemental pollutants lead to inflammation and then fibrosis in sterile condition, meaning without a role of micro-organism. Lung administration of Bleomycin in mice is a good model to define what are the endogenous molecules or danger signals and associated pathways. We have identified extracellular ATP and uric acid as danger signals released by stressed or damaged cells and able to produce pro-inflammatory interleukin-1β through activation of a cytoplasmic complex called the Nlrp3 inflammasome. We then became interested in the molecular mechanism of particle-induced Nlrp3 inflammasome activation in vitro. We demonstrate that particles such as silica or alum hydroxide lead to endogenous ATP release and further purinergic signaling via an autocrine/paracrine manner. We identified purinergic signaling as an essential triggering of interleukin-1β maturation in response to particles. As a whole, the work presented here highlights the critical role of two endogenous molecules, ATP and uric acid, in the Nlrp3-mediated immune response.
