Serum amyloid A chemoattracts immature dendritic cells and indirectly provokes monocyte chemotaxis by induction of cooperating CC and CXC chemokines

Serum amyloid A (SAA) is an acute phase protein that is upregulated in inflammatory diseases and chemoattracts monocytes, lymphocytes, and granulocytes via its G protein‐coupled receptor formyl peptide receptor like 1/formyl peptide receptor 2 (FPRL1/FPR2). Here, we demonstrated that the SAA1α isoform also chemoattracts monocyte‐derived immature dendritic cells (DCs) in the Boyden and μ‐slide chemotaxis assay and that its chemotactic activity for monocytes and DCs was indirectly mediated via rapid chemokine induction. Indeed, SAA1 induced significant amounts (≥5 ng/mL) of macrophage inflammatory protein‐1α/CC chemokine ligand 3 (MIP‐1α/CCL3) and interleukin‐8/CXC chemokine ligand 8 (IL‐8/CXCL8) in monocytes and DCs in a dose‐dependent manner within 3 h. However, SAA1 also directly activated monocytes and DCs for signaling and chemotaxis without chemokine interference. SAA1‐induced monocyte migration was nevertheless significantly prevented (60–80% inhibition) in the constant presence of desensitizing exogenous MIP‐1α/CCL3, neutralizing anti‐MIP‐1α/CCL3 antibody, or a combination of CC chemokine receptor 1 (CCR1) and CCR5 antagonists, indicating that this endogenously produced CC chemokine was indirectly contributing to SAA1‐mediated chemotaxis. Further, anti‐IL‐8/CXCL8 antibody neutralized SAA1‐induced monocyte migration, suggesting that endogenous IL‐8/CXCL8 acted in concert with MIP‐1α/CCL3. This explained why SAA1 failed to synergize with exogenously added MIP‐1α/CCL3 or stromal cell‐derived factor‐1α (SDF‐1α)/CXCL12 in monocyte and DC chemotaxis. In addition to direct leukocyte activation, SAA1 induces a chemotactic cascade mediated by expression of cooperating chemokines to prolong leukocyte recruitment to the inflammatory site.