NLRP3 inflammasome couples purinergic signaling with activation of the complement cascade for the optimal release of cells from bone marrow

Stimulation of almost all mammalian cell types leads to the release of cellular ATP and autocrine feedback through a diverse array of purinergic receptors. Depending on the types of purinergic receptors that are involved, autocrine signalling can promote or inhibit cell activation and fine-tune functional responses. Recent work has shown that autocrine signalling is an important checkpoint in immune cell activation and allows immune cells to adjust their functional responses based on the extracellular cues provided by their environment. This Review focuses on the roles of autocrine purinergic signalling in the regulation of both innate and adaptive immune responses and discusses the potential of targeting purinergic receptors for treating immune-mediated disease.

All hematopoietic and immune cells are continuously generated by hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) through highly organized process of stepwise lineage commitment. In the steady state, HSCs are mostly quiescent, while HPCs are actively proliferating and contributing to daily hematopoiesis. In response to hematopoietic challenges, e.g., life-threatening blood loss, infection, and inflammation, HSCs can be activated to proliferate and engage in blood formation. The HSC activation induced by hematopoietic demand is mediated by direct or indirect sensing mechanisms involving pattern recognition receptors or cytokine/chemokine receptors. In contrast to the hematopoietic challenges with obvious clinical symptoms, how the aging process, which involves low-grade chronic inflammation, impacts hematopoiesis remains undefined. Herein, we summarize recent findings pertaining to functional alternations of hematopoiesis, HSCs, and the bone marrow (BM) microenvironment during the processes of aging and inflammation and highlight some common cellular and molecular changes during the processes that influence hematopoiesis and its cells of origin, HSCs and HPCs, as well as the BM microenvironment. We also discuss how age-dependent alterations of the immune system lead to subclinical inflammatory states and how inflammatory signaling might be involved in hematopoietic aging. Our aim is to present evidence supporting the concept of “Inflamm-Aging,” or inflammation-associated aging of hematopoiesis.

Inflammation is triggered by a repertoire of receptors detecting infections and damages. Some of these receptors directly bind microbial ligands, while others recognize endogenous molecules exposed under stress conditions, including infections. Most of these receptors can be engaged by a relatively limited number of stimuli. Differently, NLRP3 acts as a broad sensor of cell homeostasis rupture and can be activated downstream of a plethora of stimuli. NLRP3 then assembles a multiprotein platform resulting in caspase-1 activation, which controls, by direct cleavage, the maturation of cytosolic pro-cytokines including pro-interleukin-1β. In addition, caspase-1 processes cytosolic gasdermin-D and unleashes its pore-forming N-terminal domain, leading to the release of mature cytosolic cytokines and alarmins, as well as pyroptotic cell lysis. Accumulating evidences of the aggravating role of NLRP3-mediated inflammation in various highly prevalent human conditions, including diabetes, neurodegenerative and cardiovascular diseases, raises a huge clinical interest. Nevertheless, the molecular mechanism governing NLRP3 activation remains insufficiently understood. In line with the detrimental consequences of NLRP3 activation illustrated by the aforementioned pathologies, this process is tightly regulated. In this review, we address the current understanding of the control of NLRP3 activity which can be divided into two coordinated processes referred to as priming and activation. In particular, we detail the emerging role of NLRP3 post-translational modifications critical in inflammasome assembly regulation.