A novel role of complement in mobilization: immunodeficient mice are poor granulocyte-colony stimulating factor mobilizers because they lack complement-activating immunoglobulins.
Complement (C) and innate immunity emerge as important and underappreciated modulators of mobilization of hematopoietic stem/progenitor cells (HSPC). We reported that (a) C becomes activated in bone marrow (BM) during granulocyte-colony-stimulating factor (G-CSF)-induced mobilization by the classic immunoglobulin (Ig)-dependent pathway and that (b) C3 cleavage fragments increase the responsiveness of HSPC to a stromal derived factor-1 gradient. Since patients suffering from severe combined immunodeficiency (SCID) mobilize poorly, we hypothesized that this could be directly linked to the lack of C activating Ig in these patients. In the current study to better elucidate the role of C activation in HSPC mobilization, we mobilized mice that lack Ig (RAG2, SCID, and Jh) by G-CSF or zymosan, compounds that activate C by the classic Ig-dependent and the alternative Ig-independent pathways, respectively. In addition, we evaluated mobilization in C5-deficient animals. Mobilization was evaluated by measuring the number of colony-forming unit-granulocyte macrophage and leukocytes circulating in peripheral blood. We found that (a) G-CSF- but not zymosan-induced mobilization was severely reduced in RAG2, SCID, and Jh mice; (b) impaired G-CSF-induced mobilization was restored after infusion of purified wild-type Ig; and (c) mobilization was severely reduced in C5-deficient mice. These data provide strong evidence that the C system plays a pivotal role in mobilization of HSPC and that egress of HSPC from BM occurs as part of an immune response. Disclosure of potential conflicts of interest is found at the end of this article.
Reca
Ryan
R
Stem Cell Institute, James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky 40202, USA.
Cramer
Daniel
D
Yan
Jun
J
Laughlin
Mary J
MJ
Janowska-Wieczorek
Anna
A
Ratajczak
Janina
J
Ratajczak
Mariusz Z
MZ
D000818:Animals; D002465:Cell Movement / Q000235:genetics / Q000276:immunology*; D003167:Complement Activation / Q000235:genetics* / Q000276:immunology*; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D019650:Hematopoietic Stem Cell Mobilization; D007136:Immunoglobulins / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D007153:Immunologic Deficiency Syndromes / Q000235:genetics* / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016513:Mice, SCID
D007136:Immunoglobulins; D016179:Granulocyte Colony-Stimulating Factor