Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Sdf1

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101859

Synonyms

Historical Background

Stromal-cell derived factor 1 (SDF-1) is a small cytokine that belongs to the chemokine family. SDF-1 was originally described as a secreted product of bone marrow stromal cell line (Tashiro et al. 1993) but has since then been shown to be produced by numerous cell types including immune cells and neurons. The gene for SDF-1 is located on human chromosome 10. In human and mouse, SDF-1 shows high identity of sequence (99%). SDF-1 belongs to the CXC chemokine subfamily, where the four conserved cysteines that form two disulfide bonds are separated by an intervening amino acid. Six protein isoforms, which arise from alternative mRNA splicing, have been described to date, which share a common N-terminal amino acid sequence but have a distinct C-terminus (Gleichmann et al. 2000; Pillarisetti and Gupta 2001; Stumm et al. 2002) (Fig. 1a).
Sdf1, Fig. 1

(a) Different stromal cell-derived factor (SDF-1) protein isoforms. All SDF-1 isoforms share the N-terminal (N-Term.) sequence (single letter amino acid code) highlighted in color while specific amino acid sequences are added on the C terminus (C-term.) depending on the isoform. Numbers correspond to the amino acid position and the length of the different CXCL12 isoforms. (b) Schematic structure of the SDF-1 protein (We are thankful to Franck Aguila for artwork)

Isoform Alpha, also named CXCL12, and isoform Beta are ubiquitously expressed, with highest levels detected in liver, pancreas, and spleen. Isoform Gamma is mainly expressed in heart, with weak expression detected in several other tissues. Isoform Delta, isoform Epsilon, and isoform Theta have highest expression levels in pancreas, with lower levels detected in heart, kidney, liver, and spleen. Most studies have focused on SDF-1α (Fig. 1b). The chemokine SDF1-α exists as a monomer or homodimer in equilibrium and has different effects. Dimer formation is induced by nonacidic pH and the presence of multivalent anions and by binding to its receptors or to heparin. This chemokine was first believed to act on a single receptor, the CXC chemokine receptor 4 (CXCR4). Since then, a second receptor has been found to be another target of SDF-1, namely CXCR7. CXCR4 activation by SDF-1 activates pertussis toxin (PTX)-sensitive G proteins, which activate at least two distinct signaling pathways (Fig. 2, see Guyon (2014)). The first pathway, involving phosphatidylinositol- 3 (PI-3) kinase and extracellular signal-regulated kinase (ERK)1⁄2, has been described in rodent astrocytes, neuronal progenitors, and cortical neurons. The other pathway involves the phospholipase Cβ whose activation leads to an increase in the intracellular calcium in astrocytes, cortical neurons, and cerebellar granule cell, as well as in primate fetal neuron and microglia. The increase in calcium leads to the activation of proline-rich tyrosine kinase (PYK2), which may itself lead to ERK1⁄2 activation. Contrary to CXCR4, coupling of CXCR7 to G proteins could not be demonstrated, and CXCR7 was first believed to be mainly involved in ligand sequestration. However, recent studies show that ligand binding to CXCR7 activates MAP kinases through Beta-arrestins.
Sdf1, Fig. 2

SDF-1 signaling. SDF-1 acts through its receptors CXCR4 and CXCR7 that can form dimers. CXCR4 stimulation leads to multiple signaling pathways depending on the cell type while CXCR7 mainly activates β-arrestin and induces SDF-1 scavenging. The dimerization of CXCR4 with CXCR7 induces receptor internalization

SDF-1 has been shown to have chemotactic properties on several immune cells, to play a major role in development, in inflammatory processes both in periphery and in the brain, and to play a physiological role in the brain both during development and in the adulthood, where it has been described to act as a neuromodulator, as detailed below (Fig. 3).
Sdf1, Fig. 3

SDF-1 functions during development (a) and in physiopathology (b)

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).

Therefore, the couple SDF-1/CXCR4 exerts neuromodulatory functions in the normal brain (Figs. 2 and 3b).

Summary

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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© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.IPMC (Institut de Pharmacologie Moléculaire et Cellulaire), UMR 7275, CNRS, UNSAValbonneFrance