title: Impaired mobilization of hematopoietic stem/progenitor cells in C5-deficient mice supports the pivotal involvement of innate immunity in this process and reveals novel promobilization effects of granulocytes.
abstract: We reported that complement cascade (CC) becomes activated in bone marrow (BM) during granulocyte colony-stimulating factor (G-CSF) mobilization of hematopoietic stem/progenitor cells (HSPCs) and showed that, although third CC component (C3)-deficient mice are easy mobilizers, fifth CC component (C5)-deficient mice mobilize very poorly. To explain this, we postulated that activation/cleavage of CC releases C3a and C5a anaphylatoxins that differently regulate mobilization. Accordingly, C3a, by enhancing responsiveness of HSPCs to decreasing concentrations of stromal-derived growth factor-1 (SDF-1) in BM, prevents mobilization and promotes their BM retention. Therefore, in this study, we focused on the mobilization-enhancing role of C5a. We found that C5a receptor (C5aR) is not expressed on the surface of HSPCs, and that C5a-mediated promobilization effects are mediated by stimulation of granulocytes. Overall, our data support the following model. First C5aR(+) granulocytes are chemoattracted by plasma C5 cleavage fragments, being the first wave of cells leaving BM. This facilitates a subsequent egress of HSPCs. In the next step, after leaving BM, granulocytes undergo degranulation in response to plasma C5a and secrete some cationic peptides (cathelicidin, beta-defensin) that, as shown here for the first time, highly enhance the responsiveness of HSPCs to plasma SDF-1 gradient. In conclusion, our data reveal the underappreciated central role of innate immunity in mobilization, in which C5 cleavage fragments through granulocytes orchestrate this process.
authors: Stem Cell Biology Program at the James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA.
authors: H M
authors: HM
authors: Lee
authors: W
authors: W
authors: Wu
authors: M
authors: M
authors: Wysoczynski
authors: R
authors: R
authors: Liu
authors: E K
authors: EK
authors: Zuba-Surma
authors: M
authors: M
authors: Kucia
authors: J
authors: J
authors: Ratajczak
authors: M Z
authors: MZ
authors: Ratajczak
mesh_terms: D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology; D054377:Chemokine CXCL12 / Q000097:blood / Q000494:pharmacology; D002633:Chemotaxis / Q000187:drug effects / Q000276:immunology; D015936:Complement C5a / Q000235:genetics* / Q000494:pharmacology; D015937:Complement C5a, des-Arginine / Q000494:pharmacology; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D006098:Granulocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D019650:Hematopoietic Stem Cell Mobilization; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000276:immunology*; D007113:Immunity, Innate / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D044087:Receptor, Anaphylatoxin C5a / Q000235:genetics; D015054:Zymosan / Q000494:pharmacology
chemical_list: D023181:Antimicrobial Cationic Peptides; D054377:Chemokine CXCL12; D015937:Complement C5a, des-Arginine; C515256:Cxcl12 protein, mouse; D044087:Receptor, Anaphylatoxin C5a; D016179:Granulocyte Colony-Stimulating Factor; D015936:Complement C5a; D015054:Zymosan