External Liver-Derived Complement and Intrinsic Present in Hematopoietic Stem/Progenitor Cells Complosome Modulate Cell Metabolism and Response to Stress

Abstract

Hematopoietic stem/progenitor cells (HSPCs) express receptors for complement cascade (ComC) cleavage fragments C3a and C5a and may respond to inflammation-related cues by sensing pathogen-associated molecular pattern molecules (PAMPs) released by pathogens as well as non-infectious danger associated molecular pattern molecules (DAMPs) or alarmin generated during stress/tissue damage sterile inflammation. To facilitate this HSPCs are equipped with C3a and C5a receptors, C3aR and C5aR, respectively, and express on the outer cell membrane and in cytosol pattern recognition receptors (PPRs) that sense PAMPs and DAMPs. Overall, danger-sensing mechanisms in HSPCs mimic those seen in immune cells, which should not surprise as hematopoiesis and the immune system develop from the same common stem cell precursor. This review will focus on the role of ComC-derived C3a and C5a that trigger nitric oxide synthetase-2 (Nox2) complex to release reactive oxygen species (ROS) that activate important cytosolic PRRs—Nlrp3 inflammasome, which orchestrates responsiveness of HSPCs to stress. Moreover, recent data indicate that in addition to circulating in peripheral blood (PB) activated liver-derived ComC proteins, a similar role plays ComC expressed and intrinsically activated in HSPCs known as “complosome”. We postulate that ComC triggered Nox2-ROS-Nlrp3 inflammasome responses, if they occur within non-toxic to cells' “hormetic range of activation”, positively regulate HSCs migration, metabolism, and proliferation. This sheds a new light on the immune-metabolic regulation of hematopoiesis. Graphical Abstract

Structure-Based Design and Synthesis of Stapled 10Panx1 Analogues for Use in Cardiovascular Inflammatory Diseases

“…No significant inhibition of HOS-induced ATP release in B16-BL6 cells was observed anymore for compound SBL-PX1-42 at a low nanomolar range (around 10 nM; Supporting Information, Figure S3), proving that this macrocyclic 10 Panx1 analogue exhibited a "U-shaped" concentration−response effect. Ushaped concentration−response curves have been previously described in the context of NLRP3 inflammasome responses 63 or when homeostasis is disrupted, 64 which may be the case in our experiments due to the use of HOS to induce the opening of Panx1 channels. To limit the number of conditions in the next sets of experiments, they were performed using the maximal and minimal concentrations at which 10 Panx1 and SBL-PX1-42 displayed the best inhibition of ATP release (i.e., 100 and 12.5 μM).…”