Innate immunity orchestrates the mobilization and homing of hematopoietic stem/progenitor cells by engaging purinergic signaling—an update

摘要

Innate immunity triggers mobilization of HSPCs. a Pro-mobilizing agents (e.g., G-CSF or AMD3100) activate innate immunity cells (granulocytes, monocytes, and dendritic cells) in the BM microenvironment to release danger-associated molecular pattern molecules (DAMPs), including extracellular ATP; proteolytic and lipolytic enzymes and ROS. b ATP released from innate immunity cells activates in autocrine/paracrine manner the Nlrp3 inflammasome after binding to P2X7 and P2X4 receptors. This event leads to caspase-1 activation and release from the innate immunity cells of active forms of IL-1β and IL-18, which, together with other DAMPs (e.g., HMGB1 and S100A9), amplify the mobilization process. Proteolytic enzymes and the lipolytic enzyme PLC-β2 disrupt the SDF-1–CXCR and VCAM-1–VLA4 anchoring mechanisms for HSPCs in BM niches and the structure of lipid rafts, respectively. In parallel on the surface of cells in the BM microenvironment, released ROS exposes neoepitope antigens, which, after the binding of IgM naturally occurring antibodies, activate the MBL pathway of ComC activation. c These innate immune responses amplified by purinergic signaling potentiate a mutual interaction between cells and crucial pathways involved in the mobilization process and are negatively regulated/controlled at Nlrp3 inflammasome level and ComC activation by extracellular adenosine (a degradation product of ATP) and the intracellular anti-inflammatory enzyme HO-1. d HSPCs are released from BM niches by a steep gradient of S1P in PB. e Also shown in this scheme, by releasing LPS, Gram-negative bacteria in the gut positively prime in innate immunity cells the Nlrp3 inflammasome complex in an LPS–TLR4-dependent manner, and increase synthesis of pro-IL-1β and pro-IL-18