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

Abstract

The mobilization of stem cells is still not well understood, despite the fact that this process is important for understanding the response of the organism to inflammation, tissue and organ injury, and pharmacological mobilization as a clinical procedure to harvest hematopoietic stem/progenitor cells (HSPCs) for hematopoietic transplantation [1, 2]. Currently, several mediators and cells have been proposed as playing a pivotal role in this phenomenon. Specifically, evidence has accumulated that this process is orchestrated by ancient evolutionary mechanisms mediated by innate immunity. All cell types belonging to the innate immunity network (granulocytes, monocytes, and dendritic cells) as well as the complement cascade (ComC) here play a crucial role [2, 3]. The ComC is a part of the innate immune system that defends against infections. However, evidence has accumulated that it has several other effects, including involvement in organ development, tissue regeneration, and stem cell trafficking [4]. Our group proposed that the release of HSPCs from bone marrow (BM) into peripheral blood (PB) is orchestrated by the induction of “sterile inflammation” in the BM microenvironment in response to infection, tissue/organ injury, strenuous exercise, or the administration of pro-mobilizing drugs [5, 6], such as cytokine granulocyte colony-stimulating factor (G-CSF) or AMD3100, a small-molecule inhibitor of the chemokine receptor CXCR4. G-CSF-induced or AMD3100induced pharmacological mobilization of HSPCs is a means of obtaining these cells in the clinic for hematopoietic transplantation. The ComC consists of zymogen proteins that become activated in a cascade-mediated manner by the (i) classical, (ii) mannan-binding lectin (MBL), or (iii) alternative pathways [4]. Our previous work demonstrated that the MBL but not the classical pathway plays a pivotal role in pharmacological mobilization with G-CSF or AMD3100 [7]. Specifically, mice deficient in the C1q protein, which initiates classical ComC activation, are good G-CSF and AMD3100 mobilizers [7, 8], in contrast to animals that are deficient in MBL or mannan-activated serum protease 2 (MASP-1) [7]. However, since MBL-KO and MASP-1KO mice still mobilize some HSPCs in response to G-CSF and AMD3100, here we asked whether the alternative pathway of ComC activation plays a compensatory role in this process. To address this question, we performed mobilization studies in factor B (FB)-deficient (FB-KO) mice. FB is a serine protease that is required for activation of the alternative ComC pathway. In contrast to the other two pathways, the alternative pathway is not triggered by antibodies or specific structures on the surface of microorganisms. Instead, it is activated by the spontaneous hydrolysis of C3 (the third component of the ComC and the most abundant complement protein present in blood plasma) [9]. 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 * Mariusz Z. Ratajczak [email protected]