Chemokines and other GPCR ligands synergize in receptor-mediated migration of monocyte-derived immature and mature dendritic cells

Mieke Gouwy; Sofie Struyf; Lien Leutenez; Noëmie Pörtner; Silvano Sozzani; Jo Van Damme

doi:10.1016/j.imbio.2013.10.004

Chemokines and other GPCR ligands synergize in receptor-mediated migration of monocyte-derived immature and mature dendritic cells

Immunobiology. 2014 Mar;219(3):218-29. doi: 10.1016/j.imbio.2013.10.004. Epub 2013 Oct 14.

Authors

Mieke Gouwy¹, Sofie Struyf¹, Lien Leutenez¹, Noëmie Pörtner¹, Silvano Sozzani², Jo Van Damme³

Affiliations

¹ Laboratory of Molecular Immunology, Rega Institute for Medical Research, Department of Microbiology and Immunology, University of Leuven, Leuven, Belgium.
² Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123 Brescia, Italy; Humanitas Clinical and Research Center, Rozzano, Italy.
³ Laboratory of Molecular Immunology, Rega Institute for Medical Research, Department of Microbiology and Immunology, University of Leuven, Leuven, Belgium. Electronic address: jo.vandamme@rega.kuleuven.be.

PMID: 24268109
DOI: 10.1016/j.imbio.2013.10.004

Abstract

Dendritic cells (DCs) are potent antigen presenting cells, described as the initiators of adaptive immune responses. Immature monocyte-derived DCs (MDDC) showed decreased CD14 expression, increased cell surface markers DC-SIGN and CD1a and enhanced levels of receptors for the chemokines CCL3 (CCR1/CCR5) and CXCL8 (CXCR1/CXCR2) compared with human CD14⁺ monocytes. After further MDDC maturation by LPS, the markers CD80 and CD83 and the chemokine receptors CXCR4 and CCR7 were upregulated, whereas CCR1, CCR2 and CCR5 expression was reduced. CCL3 dose-dependently synergized with CXCL8 or CXCL12 in chemotaxis of immature MDDC. CXCL12 augmented the CCL3-induced ERK1/2 and Akt phosphorylation in immature MDDC, although the synergy between CCL3 and CXCL12 in chemotaxis of immature MDDC was dependent on the Akt signaling pathway but not on ERK1/2 phosphorylation. CCL2 also synergized with CXCL12 in immature MDDC migration. Moreover, two CXC chemokines not sharing receptors (CXCL12 and CXCL8) cooperated in immature MDDC chemotaxis, whereas two CC chemokines (CCL3 and CCL7) sharing CCR1 did not. Further, the non-chemokine G protein-coupled receptor ligands chemerin and fMLP synergized with respectively CCL7 and CCL3 in immature MDDC signaling and migration. Finally, CXCL12 and CCL3 did not cooperate, but CXCL12 synergized with CCL21 in mature MDDC chemotaxis. Thus, chemokine synergy in immature and mature MDDC migration is dose-dependently regulated by chemokines via alterations in their chemokine receptor expression pattern according to their role in immune responses.

Keywords: BCA; CAM; CC chemokine ligand; CCL; CI; CXC chemokine ligand; CXCL; Chemoattractants; ERK; G protein-coupled receptor; GAG; GM-CSF; GPCR; LPS; MACS; MAPK; MDDC; MFI; Maturation; Migration; PBMC; PHA; Receptor expression; SEM; Signal transduction; Synergy; bicinchoninic acid; cell-adhesion molecules; chemotactic index; extracellular signal-regulated kinase; glycosaminoglycans; granulocyte-macrophage colony stimulating factor; lipopolysaccharide; magnetic cell sorting; mean fluorescence intensity; mitogen-activated protein kinase; monocyte-derived dendritic cells; peripheral blood mononuclear cells; phytohemagglutinin; standard error of the mean.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptive Immunity
Antigens, CD / metabolism
Cell Differentiation
Cells, Cultured
Chemokines / metabolism*
Chemotaxis
Dendritic Cells / immunology*
Humans
Immunity, Innate
Monocytes / immunology*
Oncogene Protein v-akt / metabolism
Receptor Cross-Talk
Receptors, Chemokine / genetics
Receptors, Chemokine / metabolism*
Receptors, G-Protein-Coupled / genetics
Receptors, G-Protein-Coupled / metabolism*
Signal Transduction

Substances

Antigens, CD
Chemokines
Receptors, Chemokine
Receptors, G-Protein-Coupled
Oncogene Protein v-akt