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Adhesion mechanisms regulating the migration of monocytes

Nature Reviews Immunology volume 4, pages 432–444 (2004)Cite this article

Key Points

  • Monocytes are progenitors of both tissue macrophage and dendritic-cell subsets.

  • Two classes of circulating monocytes have been identified; these have different migration properties and chemokine-receptor expression patterns.

  • The trafficking of monocytes into tissues requires the orchestrated activation of integrins by specific chemokines.

  • Signal transduction induced by chemokines targets cytosolic integrin-activating proteins, such as RHOA, RAP1, talin or PYK2, which results in cell adhesion to the blood-vessel wall.

  • Transendothelial migration of adherent monocytes requires polarization of the adherent monocytes and remodelling of the endothelial-cell junctions.

  • The trafficking of monocytes to their final tissue depends on chemotactic gradients and specific expression of adhesion molecules, which are regulated by inflammation.

Abstract

Because of their phagocytic activity and their ability to differentiate into antigen-presenting cells, monocytes participate in both innate and adaptive immune responses. They derive from bone-marrow progenitor cells, circulate in the blood as monocytes and differentiate into tissue macrophages or myeloid dendritic cells in the periphery. After activation by an antigenic challenge in the tissues, they can contribute to the local resolution of the injury or can migrate farther to secondary lymphoid organs. Recruitment of these cells from the blood to the tissue and from the tissue to the lymph nodes requires orchestrated adhesive interactions between leukocytes and the vascular or lymphatic endothelium. Here, we discuss the signals by which chemokines regulate the leukocyte-adhesion molecules that are essential for transendothelial migration, and we describe the routes taken by monocytes and myeloid dendritic cells to reach their final destination.

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Figure 1: Origin and haematopoietic differentiation of myeloid antigen-presenting cells.
Figure 2: Integrin activation and clustering during leukocyte migration.
Figure 3: Extravasation of leukocytes from a blood vessel into lymph-node tissue.
Figure 4: Chemokine-driven migration of monocytes and DC progenitors.
Figure 5: Adhesion molecules involved in the migration of monocytes to non-inflamed and inflamed tissues.

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Acknowledgements

This work was supported by grants from the Swiss National Science Foundation and the Ligne National Centre Le Cancer. We thank B. Wehrle-Haller for his valuable advice and suggestions concerning integrin activation.

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Authors and Affiliations

  1. Department of Pathology and Immunology, Centre Medical Universitaire, 1 Rue Michel-Servet, Geneva, 1204, Switzerland

    Beat A. Imhof & Michel Aurrand-Lions

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  1. Beat A. Imhof
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  2. Michel Aurrand-Lions
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Correspondence to Beat A. Imhof.

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DATABASES

Entrez Gene

α4β1-integrin

α5β1-integrin

α6β1-integrin

αMβ2-integrin

αXβ2-integrin

afadin

CASK

CCL2

CCL3

CCL5

CCL21

CCR2

CCR5

CCR7

CD14

CD16

CD43

CD44

CD62L

CD99

CDC42

citron kinase

cingulin

connexin 43

CX3CL1

CX3CR1

CXCL8

CXCL9

CXCL12

CXCL14

DC-SIGN

E-selectin

FAK

GSK3β

HRAS

ICAM1

ICAM2

JAM-A

JAM-B

JAM-C

LFA1

LGL

occludin

PAR3

PAR6

PECAM1

PI3K

PKC-ζ

P-selectin

PYK2

RAC

RAP1

RAP2

RAPL

RHOA

rhotekin

ROCK1

SMURF1

SPA1

syndecan 1

syndecan 2

syndecan 4

talin

VCAM1

VE-cadherin

ZO1

Glossary

GLY-PHE-PHE-LYS-ARG MOTIF

A conserved amino-acid motif present in the cytoplasmic domain of the α-chains of integrins. It enables the α- and β-chain of an integrin to be held in close contact, which then keeps the extracellular ligand-binding domain in a folded inactive form. Lysines (amino acids proximal to the Gly-Phe-Phe-Lys-Arg motif) are essential for the interaction of the integrin α-chain with RAPL. The binding of RAPL contributes to the spatial separation of the cytoplasmic domains of the integrin chains, allowing the unfolding of the extracellular portion into a functional ligand-binding integrin.

ASN-PRO-XAA-TYR/PHE MOTIF

A conserved amino-acid motif present in the cytoplasmic domain of the β-chains of integrins. It is a docking sequence for talin. Talin–integrin interactions mediate integrin activation. It is probable (but not yet experimentally proven) that this occurs through facilitating an optimal spatial separation of the cytoplasmic domains of the integrin chains, thereby allowing the unfolding of the extracellular portion into a functional ligand-binding integrin.

MEMBRANE RUFFLING

A cellular zone undergoing rapid reorganization of the plasma membrane and the actin cytoskeleton. Membrane ruffling often precedes the formation of a lamellipodium.

LAMELLIPODIUM

A flattened projection protruding from the anterior region of a cell. It is an actin-rich zone that is formed in response to chemokine signals, and it propels a migrating cell forward.

POLARITY COMPLEX

Polarity complex molecules were first discovered in Drosophila melanogaster and Caenorhabditis elegans. They are required for the development of anterior–posterior polarity in leukocytes and apical–basal polarity in epithelial and endothelial cells. In migrating cells, some of these complexes are enriched in the lamellipodium.

FOCAL ADHESION COMPLEXES

The closest contact sites of a cell with its environment, which are formed by integrin clustering. The integrins link the extracellular environment to the actin cytoskeleton by a complex assembly of adaptor proteins.

UROPOD

A structure formed at the posterior of a migrating leukocyte. Adhesion molecules, such as intercellular adhesion molecule 1 (ICAM1) or CD44, are enriched in this zone.

DIAPEDESIS

The last step in the leukocyte–endothelial adhesion cascade. The cascade includes tethering, triggering, tight adhesion and transmigration. Diapedesis is the migration of leukocytes across the endothelium, which occurs by squeezing through the junctions between adjacent endothelial cells.

DEFENSINS

Defensins are small (2–6 kDa) cationic microbicidal peptides that participate in innate immunity. Their tertiary structures are stabilized by intradisulphide bridges and clusters of positively charged amino acids, which resemble those found in chemokines. Several defensins have chemotactic activity for leukocytes.

OP/OP MICE

A inbred strain of mice that suffer from osteopetrosis. The defect has been localized to the gene encoding macrophage colony-stimulating factor.

THIOGLYCOLLATE-INDUCED PERITONITIS

Inflammation of the peritoneum induced by sterile injection of thioglycollate. This results in the sequential recruitment of granulocytes (within hours), monocytes (within 2 days) and lymphocytes (after 2–3 days). It is widely used to study acute inflammation.

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Imhof, B., Aurrand-Lions, M. Adhesion mechanisms regulating the migration of monocytes. Nat Rev Immunol 4, 432–444 (2004). https://doi.org/10.1038/nri1375

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  • DOI: https://doi.org/10.1038/nri1375

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