Stromal cell-derived factor 1

Last updated

CXCL12
Protein CXCL12 PDB 1a15.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases CXCL12 , IRH, PBSF, SCYB12, SDF1, TLSF, TPAR1, C-X-C motif chemokine ligand 12
External IDs OMIM: 600835; MGI: 103556; HomoloGene: 128606; GeneCards: CXCL12; OMA:CXCL12 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

6387

20315

Ensembl

ENSG00000107562

ENSMUSG00000061353

UniProt

P48061

P40224

RefSeq (mRNA)

NM_199168
NM_000609
NM_001033886
NM_001178134
NM_001277990

NM_001012477
NM_013655
NM_021704

RefSeq (protein)

NP_000600
NP_001029058
NP_001171605
NP_001264919
NP_954637

NP_001012495
NP_038683
NP_068350

Location (UCSC) Chr 10: 44.37 – 44.39 Mb Chr 6: 117.15 – 117.16 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

The stromal cell-derived factor 1 (SDF-1), also known as C-X-C motif chemokine 12 (CXCL12), is a chemokine protein that in humans is encoded by the CXCL12 gene on chromosome 10. [5] It is ubiquitously expressed in many tissues and cell types. [6] Stromal cell-derived factors 1-alpha and 1-beta are small cytokines that belong to the chemokine family, members of which activate leukocytes and are often induced by proinflammatory stimuli such as lipopolysaccharide, TNF, or IL1. The chemokines are characterized by the presence of 4 conserved cysteines that form 2 disulfide bonds. They can be classified into 2 subfamilies. In the CC subfamily, the cysteine residues are adjacent to each other. In the CXC subfamily, they are separated by an intervening amino acid. The SDF1 proteins belong to the latter group. [5] CXCL12 signaling has been observed in several cancers. [7] [8] The CXCL12 gene also contains one of 27 SNPs associated with increased risk of coronary artery disease. [9]

Structure

Gene

The CXCL12 gene resides on chromosome 10 at the band 10q11.21 and contains 4 exons.. [10] This gene produces 7 isoforms through alternative splicing. [11]

Protein

This protein belongs to the intercrine alpha (chemokine CXC) family. [11] SDF-1 is produced in two forms, SDF-1α/CXCL12a and SDF-1β/CXCL12b, by alternate splicing of the same gene. [12] Chemokines are characterized by the presence of four conserved cysteines, which form two disulfide bonds. The CXCL12 proteins belong to the group of CXC chemokines, whose initial pair of cysteines are separated by one intervening amino acid. In addition, the first 8 residues of the CXCL12 N-terminal serve as a receptor binding site, though only Lys-1 and Pro-2 directly participated in activating the receptor. Meanwhile, the RFFESH motif (residues 12-17) in the loop region function as a docking site for CXCL12 receptor binding. [13]

Function

CXCL12 is expressed in many tissues in mice including brain, thymus, heart, lung, liver, kidney, spleen, platelets and bone marrow. [14] [15] CXCL12 is strongly chemotactic for lymphocytes. [16] [17] [18] [19] During embryogenesis, it directs the migration of hematopoietic cells from fetal liver to bone marrow and the formation of large blood vessels. It has also been shown that CXCL12 signalling regulates the expression of CD20 on B cells. CXCL12 is also chemotactic for mesenchymal stem cells and is expressed in the area of inflammatory bone destruction, where it mediates their suppressive effect on osteoclastogenesis. [20]

In adulthood, CXCL12 plays an important role in angiogenesis by recruiting endothelial progenitor cells (EPCs) from the bone marrow through a CXCR4 dependent mechanism. [21]

CXCR4, previously called LESTR or fusin, is the receptor for CXCL12. [16] This CXCL12-CXCR4 interaction used to be considered exclusive (unlike for other chemokines and their receptors), but recently, it was suggested that CXCL12 may also bind the CXCR7 receptor (now called ACKR3). [22] [23] [24] By blocking CXCR4, a major coreceptor for HIV-1 entry, CXCL12 acts as an endogenous inhibitor of CXCR4-tropic HIV-1 strains. [25]

CNS

During embryonic development, CXCL12 plays a role in cerebellar formation through the migration of neurons. [26] Within the CNS, CXCL12 contributes to cell proliferation, neurogenesis (nervous tissue development and growth), as well as neuroinflammation. Neural progenitor cells (NPCs) are stem cells that differentiate into glial and neuronal cells. CXCL12 promotes their migration to lesion sites within the brain, specifically over extensive ranges. Once at the site of damage, NPCs may begin stem cell based tissue repair to the lesion. [27] The CXCL12/CXCR4 axis provides guidance cues for axons and neurites hence promoting neurite outgrowth (neurons forming projections) and neurogenesis. [28] Like other chemokines, CXCL12 is involved with cell migration that contributes to inflammation. In regards to the CNS, CXCL12 plays a role in neuroinflammation by attracting leukocytes across the blood brain barrier. [27] however, excessive production and accumulation of CXCL12 can become toxic and the inflammation produced may result in serious consequences. [29]

Clinical significance

In humans, CXCL12 has been implicated in a wide variety of biomedical conditions involving several organ systems. [30] Furthermore, CXCL12 signaling in conjunction with CXCR7 signaling has been implicated in the progression of pancreatic cancer. [7] In the urinary tract system, methylation of the CXCL12 promoter and expression of PD-L1 may be powerful prognostic biomarkers for biochemical recurrence in prostate carcinoma patients after radical prostatectomy, and further studies are ongoing to confirm if CXCL12 methylation may aid in active surveillance strategies. [31] In the field of oncology, melanoma associated fibroblasts are stimulated by stimulation of the A2B adenosine receptor followed by stimulation of fibroblast growth factor and increased expression of CXCL12. [8]

Clinical marker

A multi-locus genetic risk score study based on a combination of 27 loci, including the CXCL12 gene, identified individuals at increased risk for both incident and recurrent coronary artery disease events, as well as an enhanced clinical benefit from statin therapy. The study was based on a community cohort study (the Malmo Diet and Cancer study) and four additional randomized controlled trials of primary prevention cohorts (JUPITER and ASCOT) and secondary prevention cohorts (CARE and PROVE IT-TIMI 22). [9]

Multiple Sclerosis

A neurological condition that results from a faulty interaction between the immune and nervous systems in multiple sclerosis. MS is characterized by demyelination of nerves due to the body's immune system attacking the CNS. Elevated levels of CXCL12 are observed in the cerebral spinal fluid of patients with MS. CXCL12 crosses the blood–brain barrier and causes neuroinflammation that contributes to axonal damage and therefore the progression of multiple sclerosis. [32] [ unreliable medical source ]

Alzheimer's disease

Though CXCL12 may be detrimental for those with MS, recent research is suggesting that this chemokine may be beneficial in decreasing the progression of patients with Alzheimer's. Alzheimer's is another neurological condition and the most common form of dementia where cognition significantly declines. One main characteristic of Alzheimer's is the accumulation of a brain plaque known as beta-amyloid. There are neuroprotective aspects of CXCL12 in mice with these plaques/Alzheimer's. PAK is a protein associated with maintaining dendritic spines, which are essential at synapses in receiving information from axons. Mislocalization of PAK occurs in patients with Alzheimer's, however pretreatment of neurons in mice with CXCL12 showed a suppression of that mislocalization. [33] [ unreliable medical source ] Additionally, this pretreatment with CXCL decreased the prevalence of apoptosis and oxidative damage normally caused by the presence of the beta-amyloid plaque. [33]

As a drug target

Chemokines and chemokine receptors, of which CXCR stands out, regulate multiple processes such as morphogenesis, angiogenesis, and immune responses and are considered potential targets for drug development. It is indicated by clinical samples that a high expression level of CXCR4 in idiopathic pulmonary fibrosis lungs. Experimental evidence further indicate that CXCR4/CXCR12 is associated with the pathogenesis of lung fibrosis. [34] In the gastrointestinal tract system, the CXCL12-CXCR4 axis is under investigation as an anti-fibrotic therapy in the treatment for chronic pancreatitis. [35] For instance, blocking CXCR4, the receptor for CXCL12, with Plerixafor (AMD-3100) increased the effectiveness of combretastatin in a mouse model of breast cancer, presumably by preventing macrophages from being recruited to tumours.[15] [16] AMD-3100 is also widely used in combination with G-CSF for mobilizing hematopoietic stem cells into the blood stream, allowing collection for bone marrow transplant. [36]

Related Research Articles

<span class="mw-page-title-main">Chemokine</span> Small cytokines or signaling proteins secreted by cells

Chemokines, or chemotactic cytokines, are a family of small cytokines or signaling proteins secreted by cells that induce directional movement of leukocytes, as well as other cell types, including endothelial and epithelial cells. In addition to playing a major role in the activation of host immune responses, chemokines are important for biological processes, including morphogenesis and wound healing, as well as in the pathogenesis of diseases like cancers.

<span class="mw-page-title-main">CXCR4</span> Protein

C-X-C chemokine receptor type 4 (CXCR-4) also known as fusin or CD184 is a protein that in humans is encoded by the CXCR4 gene. The protein is a CXC chemokine receptor.

Lymphotoxin is a member of the tumor necrosis factor (TNF) superfamily of cytokines, whose members are responsible for regulating the growth and function of lymphocytes and are expressed by a wide variety of cells in the body.

<span class="mw-page-title-main">CCL7</span> Mammalian protein found in Homo sapiens

Chemokine ligand 7 (CCL7) is a small cytokine that was previously called monocyte-chemotactic protein 3 (MCP3). CCL7 is a small protein that belongs to the CC chemokine family and is most closely related to CCL2.

<span class="mw-page-title-main">CCL18</span> Mammalian protein found in Homo sapiens

Chemokine ligand 18 (CCL18) is a small cytokine belonging to the CC chemokine family. The functions of CCL18 have been well studied in laboratory settings, however the physiological effects of the molecule in living organisms have been difficult to characterize because there is no similar protein in rodents that can be studied. The receptor for CCL18 has been identified in humans only recently, which will help scientists understand the molecule's role in the body.

<span class="mw-page-title-main">CXCL9</span> Mammalian protein found in Homo sapiens

Chemokine ligand 9 (CXCL9) is a small cytokine belonging to the CXC chemokine family that is also known as monokine induced by gamma interferon (MIG). The CXCL9 is one of the chemokine which plays role to induce chemotaxis, promote differentiation and multiplication of leukocytes, and cause tissue extravasation.

<span class="mw-page-title-main">CXCL1</span> Mammalian protein found in Homo sapiens

The chemokine ligand 1 (CXCL1) is a small peptide belonging to the CXC chemokine family that acts as a chemoattractant for several immune cells, especially neutrophils or other non-hematopoietic cells to the site of injury or infection and plays an important role in regulation of immune and inflammatory responses. It was previously called GRO1 oncogene, GROα, neutrophil-activating protein 3 (NAP-3) and melanoma growth stimulating activity, alpha (MGSA-α). CXCL1 was first cloned from a cDNA library of genes induced by platelet-derived growth factor (PDGF) stimulation of BALB/c-3T3 murine embryonic fibroblasts and named "KC" for its location in the nitrocellulose colony hybridization assay. This designation is sometimes erroneously believed to be an acronym and defined as "keratinocytes-derived chemokine". Rat CXCL1 was first reported when NRK-52E cells were stimulated with interleukin-1β (IL-1β) and lipopolysaccharide (LPS) to generate a cytokine that was chemotactic for rat neutrophils, cytokine-induced neutrophil chemoattractant (CINC). In humans, this protein is encoded by the gene CXCL1 and is located on human chromosome 4 among genes for other CXC chemokines.

<span class="mw-page-title-main">CXCL2</span> Mammalian protein found in Homo sapiens

Chemokine ligand 2 (CXCL2) is a small cytokine belonging to the CXC chemokine family that is also called macrophage inflammatory protein 2-alpha (MIP2-alpha), Growth-regulated protein beta (Gro-beta) and Gro oncogene-2 (Gro-2). CXCL2 is 90% identical in amino acid sequence as a related chemokine, CXCL1. This chemokine is secreted by monocytes and macrophages and is chemotactic for polymorphonuclear leukocytes and hematopoietic stem cells. The gene for CXCL2 is located on human chromosome 4 in a cluster of other CXC chemokines. CXCL2 mobilizes cells by interacting with a cell surface chemokine receptor called CXCR2.

<span class="mw-page-title-main">CXCL5</span> Mammalian protein found in Homo sapiens

C-X-C motif chemokine 5 is a protein that in humans is encoded by the CXCL5 gene.

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<span class="mw-page-title-main">C-C chemokine receptor type 7</span> Protein-coding gene in the species Homo sapiens

C-C chemokine receptor type 7 is a protein that in humans is encoded by the CCR7 gene. Two ligands have been identified for this receptor: the chemokines ligand 19 (CCL19/ELC) and ligand 21 (CCL21). The ligands have similar affinity for the receptor, though CCL19 has been shown to induce internalisation of CCR7 and desensitisation of the cell to CCL19/CCL21 signals. CCR7 is a transmembrane protein with 7 transmembrane domains, which is coupled with heterotrimeric G proteins, which transduce the signal downstream through various signalling cascades. The main function of the receptor is to guide immune cells to immune organs by detecting specific chemokines, which these tissues secrete.

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<span class="mw-page-title-main">CXCR6</span> Mammalian protein found in Homo sapiens

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<span class="mw-page-title-main">Robyn S. Klein</span> American neuroimmunologist

Robyn S. Klein is an American neuroimmunologist as well as the Vice Provost and Associate Dean for Graduate Education at Washington University in St. Louis. Klein is also a professor in the Departments of Medicine, Anatomy & Neurobiology, and Pathology & Immunology. Her research explores the pathogenesis of neuroinflammation in the central nervous system by probing how immune signalling molecules regulate blood brain barrier permeability. Klein is also a fervent advocate for gender equity in STEM, publishing mechanisms to improve gender equity in speakers at conferences, participating nationally on gender equity discussion panels, and through service as the president of the Academic Women’s Network at the Washington University School of Medicine.

References

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  20. ↑ Takano T, Li YJ, Kukita A, Yamaza T, Ayukawa Y, Moriyama K, Uehara N, Nomiyama H, Koyano K, Kukita T (2014). "Mesenchymal stem cells markedly suppress inflammatory bone destruction in rats with adjuvant-induced arthritis". Laboratory Investigation. 94 (3): 286–96. doi: 10.1038/labinvest.2013.152 . PMID   24395111.
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  31. ↑ Goltz D, Holmes EE, Gevensleben H, Sailer V, Dietrich J, Jung M, Röhler M, Meller S, Ellinger J, Kristiansen G, Dietrich D (July 2016). "CXCL12 promoter methylation and PD-L1 expression as prognostic biomarkers in prostate cancer patients". Oncotarget. 7 (33): 53309–53320. doi:10.18632/oncotarget.10786. PMC   5288188 . PMID   27462860.
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  33. 1 2 Raman D, Milatovic SZ, Milatovic D, Splittgerber R, Fan GH, Richmond A (November 2011). "Chemokines, macrophage inflammatory protein-2 and stromal cell-derived factor-1α, suppress amyloid β-induced neurotoxicity". Toxicology and Applied Pharmacology. 256 (3): 300–13. Bibcode:2011ToxAP.256..300R. doi:10.1016/j.taap.2011.06.006. PMC   3236026 . PMID   21704645.
  34. ↑ Li F, Xu X, Geng J, Wan X, Dai H (March 2020). "The autocrine CXCR4/CXCL12 axis contributes to lung fibrosis through modulation of lung fibroblast activity". Experimental and Therapeutic Medicine. 19 (3): 1844–1854. doi:10.3892/etm.2020.8433. PMC   7027131 . PMID   32104240.
  35. ↑ Neesse A, Ellenrieder V (September 2016). "NEMO-CXCL12/CXCR4 axis: a novel vantage point for antifibrotic therapies in chronic pancreatitis?". Gut. 66 (2): gutjnl–2016–312874. doi:10.1136/gutjnl-2016-312874. PMID   27590996. S2CID   3493909.
  36. ↑ De Clercq E. (2019) Mozobil(R) (Plerixafor, AMD3100), 10 years after its approval by the US Food and Drug Administration. Antivir Chem Chemother 27:1.

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