SDF-1 in Development
Deletion of the genes encoding for SDF-1 or its receptor CXCR4 is lethal for mice soon after birth, with severe abnormalities affecting many organs, including the hematopoietic system (where SDF-1 is required for B-cell lymphopoiesis), the bone marrow (where it impacts myelopoiesis), the cardiovascular system (where it is involved in heart ventricular septum formation), and the brain (Nagasawa et al. 1996; Tachibana et al. 1998; Zou et al. 1998) (Fig. 3a). In the brain, the SDF-1/CXCR4 system plays a major role, particularly in neurogenesis (Ma et al. 1998; Zou et al. 1998; Lu et al. 2002) controlling stem cell migration, axonal guidance, and neurite outgrowth (Xiang et al. 2002; Pujol et al. 2005). In mice lacking SDF-1 or CXCR4, migration of granule cell precursors out of the external germinal layer occurs prematurely, resulting in abnormal development of the cerebellum (Ma et al. 1998). SDF-1/CXCR4 signaling also controls the migratory stream of granule cell precursors from the primary germinal zone toward the dentate gyrus (Bagri et al. 2002; Lu et al. 2002) and migration and layer-specific integration of CXCR4-expressing interneurons during neocortex development (Stumm et al. 2003).
SDF-1 in the Immune System
In the immune system, the binding of SDF-1 to CXCR4/CD184 induces intracellular signaling through several divergent pathways initiating signals related to chemotaxis, low levels of SDF-1 (100 ng/ml) being attractive but higher levels (1 mg/ml) being repulsive for T cells (Zlatopolskiy and Laurence 2001); cell survival and/or proliferation; increase in intracellular calcium; and gene transcription. CXCR4 is expressed on multiple cell types including lymphocytes, hematopoietic stem cells, endothelial and epithelial cells, and cancer cells (Fig. 3b).
SDF-1 in Pathology
The SDF-1/CXCR4 axis is involved in tumor progression, angiogenesis, metastasis, and cell survival (Fig. 3b). SDF-1 also plays a major role in inflammation as it mediates local immune responses as well as attracting leukocytes which are believed to migrate along a concentration gradient of chemokine to their target. SDF-1/CXCR4 is also involved in cardiovascular diseases, including myocardial infarction and its underlying pathologies such as atherosclerosis and injury-induced vascular restenosis. It would play a protective role after myocardial infarction (Doring et al. 2014). In the brain, SDF-1α and β are involved in the inflammatory response after a LPS injection or a focal ischemia (Stumm et al. 2002). SDF-1 can also attract leucocyte across the blood brain barrier. In Alzheimer’s disease in the vicinity of the amyloid plaques, SDF-1 attracts and/or activates local glial cells. As the glycoprotein gp120 from the envelope of HIV-1 binds directly to CXCR4 and has direct neurotoxic effects, CXCR4 is likely to be crucial for different aspects of CNS HIV infection and the development of AIDS dementia, and SDF-1 could have neuroprotective effects in this context as well as in other forms of damage.
SDF-1 in Neuronal Activity
Aside from a role in CNS development and pathology, constitutive expression of SDF-1 and its receptor CXCR4 has been demonstrated in different cell types of the adult brain including endothelial, glial, and notably neuronal cells (Ohtani et al. 1998; Stumm et al. 2002; Banisadr et al. 2003; Bonavia et al. 2003; Lazarini et al. 2003). In situ hybridization and immunocytochemistry showed that CXCR4 neuronal expression was found in many different brain areas, notably cerebral cortex, globus pallidus, caudate putamen and substantia innominata, supraoptic and paraventricular hypothalamic nuclei (Banisadr et al. 2003), lateral hypothalamus (where CXCR4 is colocalized with neurons expressing the melanin-concentrating hormone, MCH), ventromedial thalamic nucleus and substantia nigra (where CXCR4 is expressed on dopaminergic neurons of the pars compacta), but also on GABAergic neurons of the pars reticulata (Guyon 2014) and in the cerebellum (where it is expressed both in Purkinje neurons and granule cells and in glial radial fibers, (Ragozzino 2002)). SDF-1 and CXCR4 proteins were found coexpressed in a number of brain regions, and several evidences suggest that they constitute together a functional receptor/ligand system in specific neuronal pathway.
CXCR4 stimulation can directly modulate ionic channel of the plasma membrane in neurons, particularly high threshold calcium channels (Guyon et al. 2008), and this could also result in the intracellular calcium increase and PYK2 activation (Lazarini et al. 2003). Finally, in primary cultures of neurons, CXCR4 can also inhibit cAMP pathways through the Gi component of GPCRs (Liu et al. 2003).
The neuromodulatory actions of SDF-1 have been found in various neuronal populations (CA1 neurons of the hippocampus, granular and Purkinje cells of the cerebellum, MCH neurons of the lateral hypothalamus, vasopressinergic neurons of the supraoptic and the paraventricular nucleus of the hypothalamus, and dopaminergic neurons of the substantia nigra) (Guyon 2014).
CXCR4 activation by its ligand can modulate neuronal activity through multiple regulatory pathways including and often combining: (1) modulation of voltage-dependent channels (sodium, potassium, and calcium); (2) activation of the G-protein-activated inward rectifier potassium (GIRK) channels; and (3) increase in neurotransmitter release (GABA, glutamate, dopamine), often via calcium-dependent mechanisms. From one structure to another, SDF-1 has often similar consequences on neuronal transmembrane currents, but through different mechanisms (Guyon 2014).
Stromal-cell derived factor 1 chemokines are small cytokines that belongs to the CXC chemokine family. Stromal-cell derived factor 1 alpha isoform (SDF-1α) also named CXCL12 has attracted much attention. By acting through activation of its receptors, CXCR4 and CXCR7, it has chemotactic properties on several immune cells, plays a major role in inflammatory processes both in periphery and the brain, and has a physiological role in the brain both during development and in the adulthood, where it has been described to act as a neuromodulator in several neuronal populations and diverse brain areas.
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