Chemotaxis, chemokine receptors and human disease

Abstract

Cell migration is involved in diverse physiological processes including embryogenesis, immunity, and diseases such as cancer and chronic inflammatory disease. The movement of many cell types is directed by extracellular gradients of diffusible chemicals. This phenomenon, referred to as "chemotaxis", was first described in 1888 by Leber who observed the movement of leukocytes toward sites of inflammation. We now know that a large family of small proteins, chemokines, serves as the extracellular signals and a family of G-protein-coupled receptors (GPCRs), chemokine receptors, detects gradients of chemokines and guides cell movement in vivo. Currently, we still know little about the molecular machineries that control chemokine gradient sensing and migration of immune cells. Fortunately, the molecular mechanisms that control these fundamental aspects of chemotaxis appear to be evolutionarily conserved, and studies in lower eukaryotic model systems have allowed us to form concepts, uncover molecular components, develop new techniques, and test models of chemotaxis. These studies have helped our current understanding of this complicated cell behavior. In this review, we wish to mention landmark discoveries in the chemotaxis research field that shaped our current understanding of this fundamental cell behavior and lay out key questions that remain to be addressed in the future.

Figure 1

(A) A model of a chemokine GPCR-mediated signaling network. (B) In a chemoattractant gradient, the polarized cells migrate toward higher chemoattractant concentration (indicated by the intensity of red color). The actin cytoskeleton, which drives extension of leading pseudopods, is indicated by green. F, front; B, back.

Figure 2

(A) The gradient sensing machinery can be studied in the absence of cell polarity and motility. When treated with latrunculin, a chemotaxing cell becomes non-polar and non-mobile. (B) The latrunculin-treated cells generate a directional biochemical response by forming PH-GFP (green) crescents toward the cAMP gradient (red). (C) A model of the cAMP receptor-mediated gradient sensing machinery that controls PIP₃ levels on the cell membrane.

Figure 3

Actin and myosin assemblies at the leading and trailing ends of a chemotaxing cell. At the front, chemokine receptor coupled with heterotrimeric G-protein controls an actin network that includes Arp2/3, WASp/Scars, CARMIL, myosin I and ADF/cofilin. At the back and sides, the receptor and G-proteins regulate actin/myosin II complexes.