Physiology

Chemokines beyond inflammation

The old adage “don't judge a book by its cover” is certainly apt when applied to chemokines. Although they were originally defined as host defence proteins, chemokines clearly have other functions — growth-regulatory and angiogenic properties, for example — that extend well beyond the regulation of leukocyte migration1,2. Moreover, chemokine receptors such as CXCR4 are important1 in the pathogenesis of the human immunodeficiency virus, HIV-1. A further level of complexity in chemokine biology is now revealed by Tachibana et al.3 and Zou et al.4 on pages 591 and of this issue. They report that deletion of the CXCR4 gene is embryologically lethal in mice, producing a multiplicity of effects including serious developmental defects in the immune, circulatory and central nervous systems. These studies expand the biological importance of chemokines, from that of simple immune modulators to a much broader biological role than was at first appreciated (Fig. 1).

Figure 1: Biological roles of the chemokine receptor CXCR4 and its ligand SDF-1.
figure1

Tachibana et al.3 and Zou et al.4 have found that mice lacking CXCR4 have a similar phenotype to those lacking SDF-1 — namely, serious developmental defects in the immune and circulatory systems. Surprisingly, the mice also show defects in the central nervous system and in the formation of blood vessels within the gastrointestinal tract, indicating that chemokines have much more widespread functions than was initially thought.

The CXCR4 chemokine receptor is expressed throughout the body, and is a co-receptor5 for cellular entry by T-cell-tropic but not macrophage-tropic strains of HIV-1. Its ligand is the stromal derived factor SDF-1 (ref. 6), which is known to be important in embryonic development7. Mice that lack the SDF-1 gene die in utero, with severe defects in the ventricular septum of the heart. They also have fewer B-lymphocyte progenitors in the liver and bone marrow, suggesting defects in the formation of red and white blood cells. An obvious question is whether deletion of the CXCR4 receptor would produce a similar profile of deficiencies, and this is now addressed by Tachibana et al. and Zou et al. Although they find that CXCR4-deficient mice have a similar phenotype to the SDF-1 knockouts, the results also hold some surprises.

The two groups show that when both copies of the CXCR4 gene are knocked out, around half the mice die in utero by the 18th day of embryological development (E18.5), the remainder dying within one hour of birth. The similarity of this phenotype to that of the SDF-1-knockout mice confirms that CXCR4 and SDF-1 are a specific receptor-ligand pair that act in cardiac and blood-cell development. But the real surprise to come from the knockout mice is that CXCR4 is involved in the embryological development of neuronal networks in the central nervous system (CNS) and in the development of blood vessels in the gastrointestinal tract.

Zou et al.4 compared brains from normal and CXCR4-deficient mice, and found abnormalities in the architecture of the cerebellum in the knockout mice. Specifically, cells from the external granule layer prematurely migrated into the internal granule layer — a process that normally does not occur until after birth. The generation of precisely formed neural networks, also called neuronal patterning, is important for proper functioning of the entire CNS, ensuring cell-to-cell communication through a system of correctly formed cellular synapses. During normal development, neurons migrate from the germinal matrix to specific positions within the CNS. Cells in the external granule layer migrate from the surface of the cerebellum, through the molecular and Purkinje-cell layers, to form the internal granule layer. Scaffolding provided by radial glia helps these granular neurons in their migration. In the CXCR4-deficient mice, however, the authors found that this orderly process is severely disrupted by the premature migration and abnormal clustering of neurons, despite the presence of intact radial glia.

Thus, the work of Zou et al. greatly extends previous studies that have shown neuronal expression of CXCR4. This receptor is clearly important in the development of the CNS, but what role could it play? There are several possibilities. First, there is compelling evidence for cross-talk between serpentine receptors8 (the superfamily to which CXCR4 belongs). Signals generated from one receptor can either stimulate or inhibit signalling by another. Thus, CXCR4 may regulate migration of cells from the external granule layer by inhibiting their ability to respond to other chemoattractants — in fact, neurons can migrate in response to chemokines9. Alternatively, SDF-1 has been shown10 to induce apoptosis in a human neuronal cell line through CXCR4, so perhaps CXCR4 aids in the apoptotic elimination of cells that have migrated incorrectly in the CNS. This would help to ensure correct neuronal patterning. To learn more, however, we need to identify the cell types in the CNS that express CXCR4 during development.

The formation of new blood vessels can be divided into three stages: vasculogenesis, which involves the maturation of mesodermal precursor cells into haemangioblasts; angiogenesis, in which these cells develop into an initial capillary network; and, finally, pruning and remodelling to form a functional circulatory network. Tachibana et al.3 show that part of this process is defective in the gastrointestinal tract of CXCR4-deficient mice. Development of the vascular system in the gastrointestinal tract of both normal and CXCR4-knockout embryos was identical initially, and a highly vascularized network was observed at E11.5. However, at E13.5 there were clear differences in the circulatory networks of the two groups. The normal embryos developed large and small branches of the superior mesenteric arteries and veins, whereas in the CXCR4-knockout animals the larger branches of these vessels were missing, even though the vessels themselves were normal. Although these deficiencies did not affect development of the gastrointestinal tract, the abnormal circulatory system in the knockout embryos led to haemorrhaging and intestinal obstruction. As expected, SDF-1-knockout animals had a similar phenotype.

The CXCR4 receptor seems to be involved in vascular development in an organ-specific way, because the vasculature of other organs — including the brain and heart — was normal. In contrast to tyrosine kinase receptors such as vascular endothelial-cell growth factor and TIE-1, which seem to be important throughout vascular development, the CXCR4 receptor has a more restricted role. It remodels and prunes vessels, leading to the formation of a correctly branched gastrointestinal circulatory network. The discovery that SDF-1 acts in vascular development is not totally surprising, because other chemokines from the same family (interleukin-8 and melanoma growth-stimulatory activity, for example) are known to be potent angiogenic factors11. However, the physiological relevance of the angiogenic properties of these chemokines is still unclear, particularly as mice that lack the interleukin-8 receptor seem to have a normal vasculature12.

The studies of Tachibana et al.3 and Zou et al.4 have revealed that CXCR4 is important in embryonic development, particularly in the formation of blood vessels in the gastrointestinal tract and in neuronal patterning within the CNS. The findings highlight new directions for chemokine research that biologists will need to consider, and they also make sense within the context of the biological properties of chemokines. As pointed out by Baggiolini2, the chemoattractant properties of chemokines would be useful during morphogenesis to keep the cells that form tissues together. This is something that chemokines do very well and, as we have seen with the CXCR4- and SDF-1-knockout mice, there are quite dramatic developmental consequences when these proteins are deleted.

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Horuk, R. Chemokines beyond inflammation. Nature 393, 524–525 (1998). https://doi.org/10.1038/31116

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