Abstract
The NLRP3 inflammasome is a protein complex involved in IL-1β and IL-18 processing that senses pathogen- and danger-associated molecular patterns (PAMPs and DAMPs). One step- or two step-models have been proposed to explain the tight regulation of IL-1β production during inflammation. Moreover, cellular stimulation triggers adenosine triphosphate (ATP) release and subsequent activation of purinergic receptors at the cell surface. Importantly some studies have reported roles for extracellular ATP, in NLRP3 inflammasome activation in response to PAMPs and DAMPs. In this mini review, we will discuss the link between active ATP release, purinergic signaling and NLRP3 inflammasome activation. We will focus on the role of autocrine or paracrine ATP export in particle-induced NLRP3 inflammasome activation and discuss how particle activators are competent to induce maturation and secretion of IL-1β through a process that involves, as a first event, extracellular release of endogenous ATP through hemichannel opening, and as a second event, signaling through purinergic receptors that trigger NLRP3 inflammasome activation. Finally, we will review the evidence for ATP as a key pro-inflammatory mediator released by dying cells. In particular we will discuss how cancer cells dying via autophagy trigger ATP-dependent NLRP3 inflammasome activation in the macrophages engulfing them, eliciting an immunogenic response against tumors.
Highlights
The NLRP3 inflammasome is a protein complex involved in IL-1β and IL-18 processing that senses pathogen- and danger-associated molecular patterns (PAMPs and DAMPs)
This second signal may be induced by a broad variety of chemically and biologically unrelated molecules classified as either pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs)
After a first signal induced by LPS triggers accumulation of pro-IL1β, exposure to high concentrations of Extracellular ATP (eATP) (5 mM) acts as a powerful second signal to elicit the processing of pro-IL-1β into mature IL-1β in murine (Perregaux and Gabel, 1994) and human macrophages (Ataman-Onal et al, 2006) via P2X7 receptor (P2X7R) signaling (Di Virgilio, 2007)
Summary
The NLRP3 inflammasome is a protein complex involved in IL-1β and IL-18 processing that senses pathogen- and danger-associated molecular patterns (PAMPs and DAMPs). Primary stimulation of human monocytes with several other PAMPs and one DAMP was sufficient to provide both the first and the second signals via a mechanism involving active release of endogenous ATP to the extracellular environment with consequent activation of the P2X7R in an autocrine loop; this allows the triggering of mature IL-1β secretion in a one step model of inflammasome activation (Piccini et al, 2008).
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