VLA-4

Integrin α4β1 (very late antigen-4) is an integrin dimer. It is composed of CD49d (alpha 4) and CD29 (beta 1). The alpha 4 subunit is 155 kDa, and the beta 1 subunit is 150 kDa.[1]

The alpha and beta subunits change conformation in response to chemokines like SDF-1 in order to interact with ligands such as VCAM-1.
Integrin alpha-4
Identifiers
SymbolITGA4
Alt. namesCD49 antigen-like family member D
NCBI gene3676
HGNC6140
OMIM192975
RefSeqNP_000876
UniProtP13612
Other data
LocusChr. 2 q31.3
Integrin beta-1
Identifiers
SymbolITGB1
Alt. symbolsCD29
Alt. namesFibronectin receptor subunit beta
NCBI gene3688
HGNC6153
OMIM135630
RefSeqNP_002202
UniProtP05556
Other data
LocusChr. 10 p11.22

Function

The integrin VLA-4 is expressed on the cell surfaces of stem cells, progenitor cells, T and B cells, monocytes, natural killer cells, eosinophils, and neutrophils. It functions to promote an inflammatory response by the immune system by assisting in the movement of leukocytes to tissue that requires inflammation.[2] It is a key player in cell adhesion.[3]

However, VLA-4 does not adhere to its appropriate ligands until the leukocytes are activated by chemotactic agents or other stimuli (often produced by the endothelium or other cells at the site of injury). VLA-4's primary ligands include VCAM-1 and fibronectin.[4] One activating chemokine is SDF-1. Following SDF-1 binding, the integrin undergoes a conformational change of the alpha and beta domains that is necessary to confer high binding affinity for the endothelial adhesion molecules. This change is achieved by talin or kindlin interacting with the parts of VLA-4 on the inside of the cell's surface.[4]

The expression of VLA-4 in the plasma membrane is regulated by different growth factors or chemokines depending on the cell type. In T cells, IL-4 down-regulates the expression of VLA-4. In CD34 positive cells, IL-3 and SCF cause up-regulation, and G-CSF causes down-regulation (stem cells are CD34 positive cells).[4]

Role in hematopoiesis

VLA-4 can be found on hematopoietic stem and progenitor cells. These cells are found in the bone marrow, as that is where they are produced, and throughout the rest of the body. VLA-4, specifically the alpha subunit, is crucial for the localization and circulation of progenitor cells. In mice, it has been shown that injected anti-alpha antibodies result in an increase in progenitor cell circulation and duration.[1] In order for stem cells to move into the peripheral blood stream, VLA-4 must be down-regulated on the cell surface of PBSCs.[5]

Clinical significance

Stem and Progenitor cells

There is possibility for stem cell therapy through stimulation the conformational change. This is currently being studied in the field. When the alpha unit was knocked out in mice, it resulted in an embryonic lethal mutation.[4]

Multiple sclerosis

In multiple sclerosis, the VLA-4 integrin is essential in the processes by which T-cells gain access to the brain. It allows the cells to penetrate the blood brain barrier that normally restricts immune cell access. It has been found that the severity of MS is positively correlated with the expression of alpha 4.[6] One approach to prevent an autoimmune reaction has been to block the action of VLA-4 (as with natalizumab) so that pathogenic T-cells are unable to enter the brain and thus unable to attack myelin protein.[7] It has been found that in mice, anti-alpha 4 integrin antibodies resulted in an increase of circulating stem cell and progenitor cells. Though this failed in initial multiple sclerosis research, it is still being investigated.[4]

Treating other inflammatory issues

VLA-4 antagonists have also shown potential for the treatment of several inflammatory disorders. In addition to MS, a humanized antibody, natalizumab, has been considered for treating asthma.[2] There was some success in the initial human trials in treating Crohn's disease-- over 40% remission was witnessed.[8] However, the usage of natalizumab, an antagonist of VLA-4 integrin, remains controversial due to several side effects including progressive multifocal leukoencephalopathy. Other allosteric antagonists have been identified that decrease VLA-4 ligand binding affinity.[9]

Chemotherapy Sensitivity

Additionally, it has been shown that VLA-4-ligand interactions can affect the sensitivity to chemotherapy in patients with malignancies in blood-forming tissue.[4]

References
  1. Yang GX, Hagmann WK (May 2003). "VLA-4 antagonists: potent inhibitors of lymphocyte migration". Medicinal Research Reviews. 23 (3): 369–92. doi:10.1002/med.10044. PMID 12647315. S2CID 42804611.
  2. Lin KC, Castro AC (August 1998). "Very late antigen 4 (VLA4) antagonists as anti-inflammatory agents". Current Opinion in Chemical Biology. 2 (4): 453–7. doi:10.1016/S1367-5931(98)80120-8. PMID 9736917.
  3. Cox, Dermot; Brennan, Marian; Moran, Niamh (October 2010). "Integrins as therapeutic targets: lessons and opportunities". Nature Reviews Drug Discovery. 9 (10): 804–820. doi:10.1038/nrd3266. ISSN 1474-1784. PMID 20885411. S2CID 21837118.
  4. Imai Y, Shimaoka M, Kurokawa M (May 2010). "Essential roles of VLA-4 in the hematopoietic system". International Journal of Hematology. 91 (4): 569–75. doi:10.1007/s12185-010-0555-3. PMID 20352381. S2CID 26908567.
  5. Gazitt Y (November 2000). "Immunologic profiles of effector cells and peripheral blood stem cells mobilized with different hematopoietic growth factors". Stem Cells. 18 (6): 390–8. doi:10.1634/stemcells.18-6-390. PMID 11072026. S2CID 24402106.
  6. Sheremata WA, Minagar A, Alexander JS, Vollmer T (November 2005). "The role of alpha-4 integrin in the aetiology of multiple sclerosis: current knowledge and therapeutic implications". CNS Drugs. 19 (11): 909–22. doi:10.2165/00023210-200519110-00002. PMID 16268663. S2CID 31963909.
  7. Paul WE (September 1993). "Infectious Diseases and the Immune System". Scientific American. 269 (3): 111–114. doi:10.1038/scientificamerican0993-90. ISBN 978-0-226-74264-9. PMID 8211095.
  8. Zollner TM, Asadullah K, Schön MP (January 2007). "Targeting leukocyte trafficking to inflamed skin: still an attractive therapeutic approach?". Experimental Dermatology. 16 (1): 1–12. doi:10.1111/j.1600-0625.2006.00503.x. PMID 17181631. S2CID 10061917.
  9. Chigaev A, Wu Y, Williams DB, Smagley Y, Sklar LA (February 2011). "Discovery of very late antigen-4 (VLA-4, alpha4beta1 integrin) allosteric antagonists". The Journal of Biological Chemistry. 286 (7): 5455–63. doi:10.1074/jbc.M110.162636. PMC 3037658. PMID 21131351.
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