Researchers from the Scripps Research Institute have established a neuroprotective role for a specific integrin receptor (α6β4 integrin) following damaging neuroinflammation, through stabilisation of the blood-brain barrier.
The α6β4 integrin protein was found to be upregulated following the initiation of multiple sclerosis-related neuroinflammation. The upregulation of α6β4 integrin correlated with a better clinical outcome in mice with the receptor protein, compared to the mice that had the α6β4 integrin gene knocked-out of their genome, leaving the mice unable to express this protein.
These α6β4 integrin knockout mice were much more susceptible to infiltration of leukocyte immune cells to the central nervous system. Such infiltration should be inhibited by the blood-brain barrier under healthy conditions.
The impact of genetically deleting endothelial β4 integrin on neuroinflammation in experimental autoimmune encephalomyelitis (EAE). Frozen brain sections taken from the β4-EC-KO and WT littermate control mice at the acute stage of EAE (day 21) were stained using antibodies specific for the inflammatory leukocyte markers MHC II, CD45, and Mac-1. Data points represent the mean ± SEM of events observed in the medulla oblongata (n = 4 mice). Scale bar = 100 μm. Credit: Welser JV, et al. CC-BY
This result correlated with a reduced expression of tight junction proteins that would normally keep potentially damaging non-central nervous system cells and proteins away from sensitive brain tissue.
Integrin receptors are bound to cell membranes and allow for the interaction of cells with the extracellular matrix (the network of proteins, polysaccharides and growth factors which surround the cells).
The binding of integrins to extracellular matrix components allows for cells to react to their external environment and translate external stimulus – like stiffness of tissue – to internal alterations in cellular gene expression.
This particular integrin protein binds to laminin, an extracellular matrix protein which forms part of the basal lamina which surrounds blood vessels and is also present in the native brain matrix. Laminin has been shown to have multiple beneficial effects for neural and vascular tissues, with promotion of new blood vessel and neuronal growth being associated with laminin expression.
These characteristics have led to the use of laminin binding domains in lab based neurovascular cell cultures. The incorporation of the peptide binding sequence for attachment of laminin to integrin receptors can promote the positive effects of laminin without actually having the protein present.
Through utilizing the peptide sequence which binds to α6β4 integrin it may be possible to use this receptor as a target for therapeutics. If a drug is able to bind to α6β4 integrin it may be able to treat or prevent the neurovascular damage associated with multiple sclerosis, and avoid the neuroinflammatory-induced degradation of axons.
Such a therapy may also be applied to other diseases which have a neuroinflammatory and neurovascular component to their pathogenesis, like Alzheimer’s disease, Parkinson’s disease or CADASIL.
Even if the α6β4 integrin receptor cannot be utilised for the successful development of a novel therapeutic, the mechanistic based discovery of α6β4 integrin action could be crucial to deciphering the underlying pathology behind neuroinflammation in neurodegenerative disease. Blood-brain barrier integrity is crucial to general health, and scientific advances such as these may lead to improved quality of life for people with neuroinflammatory diseases.