Inflammasomes and the Maintenance of Hematopoietic Homeostasis: New Perspectives and Opportunities

Abstract

Hematopoietic stem cells (HSCs) regularly produce various blood cells throughout life via their self-renewal, proliferation, and differentiation abilities. Most HSCs remain quiescent in the bone marrow (BM) and respond in a timely manner to either physiological or pathological cues, but the underlying mechanisms remain to be further elucidated. In the past few years, accumulating evidence has highlighted an intermediate role of inflammasome activation in hematopoietic maintenance, post-hematopoietic transplantation complications, and senescence. As a cytosolic protein complex, the inflammasome participates in immune responses by generating a caspase cascade and inducing cytokine secretion. This process is generally triggered by signals from purinergic receptors that integrate extracellular stimuli such as the metabolic factor ATP via P2 receptors. Furthermore, targeted modulation/inhibition of specific inflammasomes may help to maintain/restore adequate hematopoietic homeostasis. In this review, we will first summarize the possible relationships between inflammasome activation and homeostasis based on certain interesting phenomena. The cellular and molecular mechanism by which purinergic receptors integrate extracellular cues to activate inflammasomes inside HSCs will then be described. We will also discuss the therapeutic potential of targeting inflammasomes and their components in some diseases through pharmacological or genetic strategies.

Hematopoiesis and innate immunity: an inseparable couple for good and bad times, bound together by an hormetic relationship

“…These observations and the fact that ROS released from mitochondria in a complosome activation-dependent manner enhances the intracellular level of Nlrp3 inflammasomes supports the concept that the complosome–Nlrp3 inflammasome interaction promotes proliferation of HSPCs [ 94 ]. In accordance with this concept, a recent report suggested that glucose influx to the developing vertebrate embryo expands murine early CD41 + HSPCs in hematopoietic organs, and this effect depends on Nlrp3 inflammasome activation and IL-1β release [ 95 ].…”

Role of Inflammasomes in Keloids and Hypertrophic Scars—Lessons Learned from Chronic Diabetic Wounds and Skin Fibrosis

“…They also regulate the immune homeostasis of the barrier epithelia (including the skin) [ 33 , 34 ]. In addition, they have also been suggested to regulate normal processes that do not relate directly to microorganisms, including the balance between erythroid and myeloid differentiation [ 35 ], normal hematopoiesis [ 36 ], hepatic metabolism [ 32 ], sterile inflammation such as that in pregnancy [ 37 ], and crosstalk with autophagy that regulates cellular integrity and prevent tumorigenesis [ 38 ]. However, similar to many other immune entities, inflammasomes can cause disease when they are dysregulated.…”

The Potential of Purinergic Signaling to Thwart Viruses Including SARS-CoV-2

“…This irreversible growth arrest of the cell was accompanied by a senescence-associated secretory phenotype (SASP) that could induce secondary senescence of endothelial cells, with an associated infiltration of macrophages and neutrophils resulting in endothelial damage and lung tissue thrombosis (115). Given involvement of the inflammasome in paracrine senescence (116) and purinergic P2Y 14 receptor modulation of stress-induced hematopoietic progenitor cell senescence (117,118), purinergic pathways may present new pharmacological avenues for controlling senescence-mediated morbidities from SARS-CoV-2 infection.…”