Complement C3a enhances CXCL12 (SDF-1)-mediated chemotaxis of bone marrow hematopoietic cells independently of C3a receptor.
Complement C3a promotes CXCL12-induced migration and engraftment of human and murine hemopoietic progenitor cells, suggesting a cross-influence between anaphylatoxin and chemokine axes. Here we have explored the underlying mechanism(s) of complement anaphylatoxin and chemokine cooperation. In addition to C3a, C3a-desArg and C4a but not C5a, are potent enhancers of CXCL12-induced chemotaxis of human and murine bone marrow (BM) stem/progenitor cells and B lineage cells. C3a enhancement of chemotaxis is chemokine specific because it is also observed for chemotaxis to CCL19 but not to CXCL13. The potentiating effect of C3a on CXCL12 is independent of the classical C3a receptor (C3aR). First, human BM CD34(+) and B lineage cells do not express C3aR by flow cytometry. Second, the competitive C3aR inhibitor SB290157 does not affect C3a-mediated enhancement of CXCL12-induced chemotaxis. Third, enhancement of chemotaxis of hemopoietic cells is also mediated by C3a-desArg, which does not bind to C3aR. Finally, C3a enhances CXCL12-induced chemotaxis of BM cells from C3aR knockout mice similar to BM cells from wild-type mice. Subsequent studies revealed that C3a increased the binding affinity of CXCL12 to human CXCR4(+)/C3aR(-), REH pro-B cells, which is compatible with a direct interaction between C3a and CXCL12. BM stromal cells were able to generate C3a, C3a-desArg, C4a, as well as CXCL12, suggesting that this pathway could function in vivo. Taken together, we demonstrate a C3a-CXCL12 interaction independent of the C3aR, which may provide a mechanism to modulate the function of CXCL12 in the BM microenvironment.
Honczarenko
Marek
M
Joint Program in Transfusion Medicine, Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, USA.
Ratajczak
Mariusz Z
MZ
Nicholson-Weller
Anne
A
Silberstein
Leslie E
LE
D000706:Anaphylatoxins / Q000378:metabolism / Q000502:physiology; D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism; D001853:Bone Marrow; D002478:Cells, Cultured; D054377:Chemokine CXCL12; D018925:Chemokines / Q000378:metabolism / Q000502:physiology; D019743:Chemokines, CXC / Q000378:metabolism / Q000502:physiology*; D002633:Chemotaxis; D015926:Complement C3a / Q000378:metabolism / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D006801:Humans; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D011951:Receptors, Complement / Q000502:physiology*; D017154:Stromal Cells / Q000378:metabolism
D000706:Anaphylatoxins; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D018925:Chemokines; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D008565:Membrane Proteins; D011951:Receptors, Complement; C085567:complement C3a receptor; D015926:Complement C3a