Extracellular Adenosine Triphosphate (eATP) and Its Metabolite, Extracellular Adenosine (eAdo), as Opposing “Yin–Yang” Regulators of Nlrp3 Inflammasome in the Trafficking of Hematopoietic Stem/Progenitor Cells

Abstract

Nlrp3 inflammasome plays a pleiotropic role in hematopoietic cells. On the one hand, physiological activation of this intracellular protein complex is crucial to maintaining normal hematopoiesis and the trafficking of hematopoietic stem progenitor cells (HSPCs). On the other hand, its hyperactivation may lead to cell death by pyroptosis, and prolonged activity is associated with sterile inflammation of the BM and, as a consequence, with the HSPCs aging and origination of myelodysplasia and leukemia. Thus, we need to understand better this protein complex’s actions to define the boundaries of its safety window and study the transition from being beneficial to being detrimental. As demonstrated, the Nlrp3 inflammasome is expressed and active both in HSPCs and in the non-hematopoietic cells that are constituents of the bone marrow (BM) microenvironment. Importantly, the Nlrp3 inflammasome responds to mediators of purinergic signaling, and while extracellular adenosine triphosphate (eATP) activates this protein complex, its metabolite extracellular adenosine (eAdo) has the opposite effect. In this review, we will discuss and focus on the physiological consequences of the balance between eATP and eAdo in regulating the trafficking of HSPCs in an Nlrp3 inflammasome-dependent manner, as seen during pharmacological mobilization from BM into peripheral blood (PB) and in the reverse mechanism of homing from PB to BM and engraftment. We propose that both mediators of purinergic signaling and the Nlrp3 inflammasome itself may become important therapeutic targets in optimizing the trafficking of HSPCs in clinical settings.

Amniotic fluid stem cell‐derived extracellular vesicles are independent metabolic units capable of modulating inflammasome activation in THP‐1 cells

“…The ability of HASC‐EVs to produce adenosine, an important modulator of inflammation 30,36 led us to hypothesize that adenosine receptor activation might be involved in inflammasome inhibition in THP‐1 cells.…”

“…However, reports in the literature claim both pro‐inflammatory and anti‐inflammatory effects for both ATP and adenosine. It is conceivable that the final effect of ATP and adenosine on the immune response depends on the balance between ATP and adenosine in the immediate vicinity of the cells 36,55 . Adenosine exerts its anti‐inflammatory effects through four cell‐surface G‐protein coupled adenosine receptors subtypes, namely A1, A2a, A2b, and A3.…”

The Yin and Yang of Immunity in Stem Cell Decision Guidance in Tissue Ecologies: An Infection Independent Perspective

“…P2YR (high affinity receptors) sense low ATP levels whereas P2XR (low affinity receptors) seems to curb the response when inflammation peaks forming an auto-regulatory loop. P2XR receptor is known to activate the inflammasome resulting in release of IL-1β ( Ratajczak and Kucia 2020 ). The resolution of this loop is mediated by action of ecto-nucleotidase enzymes which convert pro-inflammatory ATP to immune-suppressive Adenosine.…”

The NLRP3 Inflammasome: Relevance in Solid Organ Transplantation

“…In this section, this review aims to briefly highlight findings from solid organ-specific fields regarding NLRP3 inflammasome involvement in either pre- or post-transplant pathology. Literature on NLRP3 inflammasome activation in the specific fields of hematopoietic stem cell transplant [ 87 , 88 , 89 ], pancreatic islet cell transplant [ 90 ], and post-transplant complications such as graft-versus-host disease and the development of myeloproliferative neoplasms [ 87 , 91 ] is abundant, and as such re-direction to the superlative existing recent review treatments of these fields is necessary.…”