ATP release and purinergic signaling: a common pathway for particle-mediated inflammasome activation

Abstract

Deposition of uric acid crystals in joints causes the acute and chronic inflammatory disease known as gout and prolonged airway exposure to silica crystals leads to the development of silicosis, an irreversible fibrotic pulmonary disease. Aluminum salt (Alum) crystals are frequently used as vaccine adjuvant. The mechanisms by which crystals activate innate immunity through the Nlrp3 inflammasome are not well understood. Here, we show that uric acid, silica and Alum crystals trigger the extracellular delivery of endogenous ATP, which just precedes the secretion of mature interleukin-1β (IL-1β) by macrophages, both events depending on purinergic receptors and connexin/pannexin channels. Interestingly, not only ATP but also ADP and UTP are involved in IL-1β production upon these Nlrp3 inflammasome activators through multiple purinergic receptor signaling. These findings support a pivotal role for nucleotides as danger signals and provide a new molecular mechanism to explain how chemically and structurally diverse stimuli can activate the Nlrp3 inflammasome.

The ecto-ATPDase CD39 is involved in the acquisition of the immunoregulatory phenotype by M-CSF-macrophages and ovarian cancer tumor-associated macrophages: Regulatory role of IL-27

“…15,56 After stimulation with LPS alone, GM-CSF-macrophages but not M-CSFmacrophage produced IL-1b. This result suggested that GM-CSF-macrophages release their endogenous ATP after LPS activation, a result in agreement with Riteau et al and Levesque et al 57,58 In the present study, the blockade of CD39 and the depletion of adenosine rendered human TAM and M-CSFmacrophages able to secrete IL-1b, a process that reflects their ability to release ATP. These results confirmed the importance of endogenous ATP for the tuning of immunostimulatory properties by human macrophages.…”

Intracellular ATP Decrease Mediates NLRP3 Inflammasome Activation upon Nigericin and Crystal Stimulation

“…Finally, decreased iATP did not raise extracellular ATP levels, but had rather the opposite effect (Supplemental Fig. 2D), thus excluding a role for extracellular ATP signaling via the ATP/P2X7 receptor axis as an explanation of the effects of lowered iATP (16).…”

Consensus guidelines for the detection of immunogenic cell death

“…141,[177][178][179] Moreover, extracellular ATP promotes the activation of the NLR family, pyrin domain containing 3 (NLRP3) inflammasome in APCs, hence stimulating the processing and release of interleukin (IL)-1b and IL-18. 119,[180][181][182][183][184][185][186][187][188][189] In line with this notion, the immunogenic potential of cells succumbing to ICD can be significantly reduced by pharmacological or genetic interventions that limit the availability of ATP in the pericellular space, such as the administration of recombinant apyrase (an ATP-degrading enzyme) or the transfection-enforced overexpression of ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1, best known as CD39), which converts ATP into ADP and AMP. 190 Intriguingly, CD39 and 5 0 -nucleotidase, ecto (NT5E, best known as CD73), which transforms AMP into adenosine, are often overexpressed by malignant tissues.…”