Abstract
Mobilization of stem cells from bone marrow (BM) into peripheral blood (PB) in response to tissue or organ injury, infections, strenuous exercise, or mobilization-inducing drugs is as we postulated result of a “sterile inflammation” in the BM microenvironment that triggers activation of the Complement Cascade (ComC). Therefore, we became interested in the role of the Nlrp3 inflammasome in this process and show for the first time that its activation in ATP-dependent manner orchestrates BM egress of hematopoietic stem/progenitor cells (HSPCs) as well as other stem cells, including mesenchymal stroma cells (MSCs), endothelial progenitor cells (EPCs), and very small embryonic-like stem cells (VSELs). To explain this extracellular ATP is a potent activator of the Nrlp3 inflammasome, which leads to the release of interleukin 1β and interleukin 18, as well as several danger-associated molecular pattern molecules (DAMPs) that activate the mannan-binding lectin (MBL) pathway of the ComC, from cells of the innate immunity network. In support of this mechanism, we demonstrate that the Nlrp3 inflammasome become activated in innate immunity cells by granulocyte colony stimulating factor (G-CSF) and AMD3100 in an ATP-dependent manner. Moreover, administration of the Nlrp3 inflammasome activator nigericin induces mobilization in mice, and the opposite effect is obtained by administration of an Nlrp3 inhibitor (MCC950) to mice mobilized by G-CSF or AMD3100. In summary, our results further support the crucial role of innate immunity, BM sterile inflammation, and novel role of the ATP–Nlrp3–ComC axis in the egress of stem cells into PB.
Original language | English |
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Pages (from-to) | 391-403 |
Number of pages | 13 |
Journal | Stem Cell Reviews and Reports |
Volume | 15 |
Issue number | 3 |
DOIs | |
State | Published - Jun 15 2019 |
Bibliographical note
Funding Information:Acknowledgements This work was supported by NIH grants 2R01 DK074720 and R01HL112788, the Stella and Henry Endowment, and the OPUS grant National Center Grant UMO-2018/29/B/NZ4/01470 to MZR and National Centre Grant OPUS grant 2016/21/B/NZ4/00201 to MK. AT was supported by NIH T32 HL134644 to MZR. AAL is supported by the University of Kentucky COBRE Early Career Program (P20 GM103527) and the NIH Grant R01 HL124266.
Funding Information:
This work was supported by NIH grants 2R01 DK074720 and R01HL112788, the Stella and Henry Endowment, and the OPUS grant National Center Grant?UMO-2018/29/B/NZ4/01470 to MZR and National Centre Grant?OPUS grant 2016/21/B/NZ4/00201 to MK. AT was supported by NIH T32 HL134644 to MZR. AAL is supported by the University of Kentucky COBRE Early Career Program (P20 GM103527) and the NIH Grant R01 HL124266.
Publisher Copyright:
© 2019, The Author(s).
Keywords
- Complement cascade
- Extracellular nucleotides
- Nlrp3 Inflammasome
- Purinergic signaling
- Stem cell mobilization
ASJC Scopus subject areas
- Cell Biology
- Cancer Research