The Nlrp3 inflammasome as a “rising star” in studies of normal and malignant hematopoiesis

Abstract

Recent investigations indicate that hematopoiesis is coregulated by innate immunity signals and by pathways characteristic of the activation of innate immunity cells that also operate in normal hematopoietic stem progenitor cells (HSPCs). This should not be surprising because of the common developmental origin of these cells from a hemato/lymphopoietic stem cell. An important integrating factor is the Nlrp3 inflammasome, which has emerged as a major sensor of changes in body microenvironments, cell activation, and cell metabolic activity. It is currently the best-studied member of the inflammasome family expressed in hematopoietic and lymphopoietic cells, including also HSPCs. It is proposed as playing a role in (i) the development and expansion of HSPCs, (ii) their release from bone marrow (BM) into peripheral blood (PB) in stress situations and during pharmacological mobilization, (iii) their homing to BM after transplantation, and (iv) their aging and the regulation of hematopoietic cell metabolism. The Nlrp3 inflammasome is also involved in certain hematological pathologies, including (i) myelodysplastic syndrome, (ii) myeloproliferative neoplasms, (iii) leukemia, and (iv) graft-versus-host disease (GvHD) after transplantation. The aim of this review is to shed more light on this intriguing intracellular protein complex that has become a "rising star" in studies focused on both normal steady-state and pathological hematopoiesis.

Nlrp3 Inflammasome Signaling Regulates the Homing and Engraftment of Hematopoietic Stem Cells (HSPCs) by Enhancing Incorporation of CXCR4 Receptor into Membrane Lipid Rafts

“…In fact, we showed in this report that Nlrp3-KO mice have reduced numbers of SKL cells as well as CFU-GM and BFU-E clonogenic progenitors in the BM microenvironment. These observations together demonstrate the important modulatory role of the Nlrp3 inflammasome in hematopoietic reconstitution [65].…”

“…eATP plays a dual role in the homing of HSPCs to BM. On the one hand, whether autocrine-secreted from transplanted HSPCs (*) or secreted in response to conditioning for transplantation from cells in the BM microenvironment (**), eATP promotes formation of membrane lipid rafts (yellow cap) on the surface of HSPCs, which assemble together the major receptors for chemoattractants (SDF-1, S1P, and eATP) (adapted from 65) for transplantation. On the basis of this finding, modulation of Nlrp3 inflammasome activity becomes a potential target for therapeutic interventions to improve clinical outcomes from hematopoietic transplantations.…”

Review of Trials Currently Testing Stem Cells for Treatment of Respiratory Diseases: Facts Known to Date and Possible Applications to COVID-19

“…In the case of hematopoietic stem / progenitor cells (HSPCs), evidence suggests that the SARS-CoV-2 virus input receptor (ACE2) and the angiotensin II receptor (AT1) are expressed and functional on the surface of these cells [86,87]. Therefore, it is possible for SARS-CoV-2 upon binding to ACE2 via the Spike protein to directly activate the Nlrp3 inflammasome, contributing to the cytokine storm, affecting the mitochondrial function, leading to cell death by pyroptosis [87][88][89][90][91][92][93]. The Nlrp3 inflammasome, which can affect various tissues and organs as well as potentially hematopoiesis [93], may be responsible for certain complications during a SARS-CoV-2 infection.…”

“…Since we know that the mitochondrial disorder caused by the overactivation of Nlrp3 inflammasome is determinant to the pathogenesis of SARS-CoV-2, Nlrp3 inflammasome inhibitors must be taken into account regarding their therapeutic applicability [87][88][89]92]. An example for this inhibitory potential is the MCC950 molecule which could affect the binding of SARS-CoV-2 to cells and inhibit the amplification of the intracellular virus, and also the ComC inhibitors that assist in modulating the activity of the innate immune system [93].…”

SARS-CoV-2 Entry Receptor ACE2 Is Expressed on Very Small CD45− Precursors of Hematopoietic and Endothelial Cells and in Response to Virus Spike Protein Activates the Nlrp3 Inflammasome

“…The Nlrp3 inflammasome triggers an inflammatory immune response via intracellular caspase 1, which leads to i) release of the potent pro-inflammatory cytokines interleukin 1β (IL-1β) and interleukin 18 (IL-18) and ii) mediates the release of several biologically active danger-associated molecular pattern molecules (DAMPs) by creating gasdermin D (GSDMD) pore channels in cell membranes [16][17][18]. This initiates a sequence of events leading to amplification of the innate immune system response and activation of its major humoral arm, the complement cascade (ComC) [19,20].…”