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

Abstract

The mechanisms that regulate egress of hematopoietic stem/progenitor cells (HSPCs) into peripheral blood (PB) in response to stress, inflammation, tissue/organ injury, or administration of mobilization-inducing drugs are still not well understood, and because of the importance of stem cell trafficking in maintaining organism homeostasis, several complementary pathways are believed to be involved. Our group proposes that mobilization of HSPCs is mainly a result of sterile inflammation in the bone marrow (BM) microenvironment in response to pro-mobilizing stimuli and that during the initiation phase of the mobilization process BM-residing cells belonging to the innate immunity system, including granulocytes and monocytes, release danger-associated molecular pattern molecules (DAMPs, also known as alarmins), reactive oxygen species (ROS), as well as proteolytic and lipolytic enzymes. These factors together orchestrate the release of HSPCs into PB. One of the most important DAMPs released in the initiation phase of mobilization is extracellular adenosine triphosphate, a potent activator of the inflammasome. As a result of its activation, IL-1β and IL-18 as well as other pro-mobilizing mediators, including DAMPs such as high molecular group box 1 (Hmgb1) and S100 calcium-binding protein A9 (S100a9), are released. These DAMPs are important activators of the complement cascade (ComC) in the mannan-binding lectin (MBL)-dependent pathway. Specifically, Hmgb1 and S100a9 bind to MBL, which leads to activation of MBL-associated proteases, which activate the ComC and in parallel also trigger activation of the coagulation cascade (CoaC). In this review, we will highlight the novel role of the innate immunity cell-expressed NLRP3 inflammasome, which, during the initiation phase of HSPC mobilization, couples purinergic signaling with the MBL-dependent pathway of the ComC and, in parallel, the CoaC for optimal release of HSPCs. These data are important to optimize the pharmacological mobilization of HSPCs.

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

“…Our already published results demonstrated that the Nlrp3 inflammasome plays a crucial role in the mobilization into PB of HSPCs and other BM-residing stem cells [62]. In support of this finding, the Nlrp3 inflammasome becomes activated during mobilization, both in innate immunity cells (granulocytes, monocytes, and dendritic cells) and in HSPCs in response to G-CSF or AMD3100.…”

“…Since egress of HSPCs into peripheral blood (PB) is mediated by induction of a state of sterile inflammation in the BM hematopoietic microenvironment due to innate immunity activation [44], we became interested in whether the Nlrp3 inflammasome plays a significant role in the mobilization process [62]. We also asked whether Nlrp3 inflammasome-mediated mechanisms play a role in the mobilization of other BM-residing stem/progenitor cells, such as mesenchymal stromal cells, endothelial progenitor cells, and very small embryonic-like stem cells.…”

Novel evidence that an alternative complement cascade pathway is involved in optimal mobilization of hematopoietic stem/progenitor cells in Nlrp3 inflammasome-dependent manner

“…Furthermore, supporting the important role of innate immunity in mobilization, we recently demonstrated involvement of the Nlrp3 inflammasome complex in the induction of "sterile" inflammation in BM, which triggers the mobilization of HSPCs [10,11]. Based on this and our previous data we become interested in a potential role of alterative pathway of ComC activation in mobilization of HSPCs.…”

Acquired Aplastic Anemia as a Clonal Disorder of Hematopoietic Stem Cells

“…In addition in pathogenesis of inflammaging are involved several danger associated molecular pattern molecules (DAMPs) including extracellular ATP, oxidatively modified DNA; and aggregated proteins released from damaged cells [105]. All these DAMPs lead to activation of the Nlrp3 inflammasome, that drives process of inflammaging in the all tissues including bone marrow [106][107][108]. Activation of Nlrp3 inflammasome leads to release from innate immunity cells two pro-inflammatory interleukins IL-1β and IL-1 [105][106][107][108].…”

“…All these DAMPs lead to activation of the Nlrp3 inflammasome, that drives process of inflammaging in the all tissues including bone marrow [106][107][108]. Activation of Nlrp3 inflammasome leads to release from innate immunity cells two pro-inflammatory interleukins IL-1β and IL-1 [105][106][107][108]. While as demonstrated IL-1β signaling decreases erythropoietin secretion in the kidney [109], IL-18 induces interferon gamma (IFN-γ) expression, which along with IL-1α synergistically inhibits erythroid colony formation [110].…”