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.
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.
Lee
H M
HM
Stem Cell Biology Program at the James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA.
Wu
W
W
Wysoczynski
M
M
Liu
R
R
Zuba-Surma
E K
EK
Kucia
M
M
Ratajczak
J
J
Ratajczak
M Z
MZ
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
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