By Angelica Michelle-Fimbres Garcia
Central to understanding Multiple Sclerosis and developing a more effective Multiple Sclerosis treatment is the network of blood vessels in the brain involved in isolating the brain from the bloodstream, known as the blood-brain barrier. Multiple Sclerosis is an autoimmune disease that results in the degradation of myelin sheaths surrounding central nervous system axons. In Multiple Sclerosis and other neuroinflammatory disorders, immune cells make it through the blood-brain barrier and attack healthy nervous tissue. Therefore, searching for solutions to a dysfunctional blood-brain barrier could illuminate potential treatment for a range of conditions such as Multiple Sclerosis, Alzheimer’s disease, and stroke that otherwise have poor outcomes.
Surprisingly, researchers are looking for answers in LXRa and LXRb receptors, which are highly concentrated in the liver but also found on the lining of the blood-brain barrier. These receptors typically stimulate the transcription of DNA into RNA and have been found to decrease neuroinflammation in past studies. Researchers from a recent study set out to find how the LXRa and LXRb receptors would affect the blood-brain barrier under neuroinflammatory conditions similar to what occurs in cases of Multiple Sclerosis.
The study began by genetically shutting down either LXRa or LXRb in vitro, so that one of the receptors was not present. Only the shut down of LXRa increased permeability of the blood-brain barrier, decreasing the expression of blood-brain barrier tight junctions that normally keep the barrier intact. Tight junctions are areas between some cells that are held tightly together by proteins and are one of the main ways the blood-brain barrier regulates what goes in and out of the brain. The absence of these tight junctions could allow unnecessary immune cells to get into the brain and cause inflammation. In addition to the loss of tight junctions, the researchers saw increased inflammation of the tissue inside the blood-brain barrier vessels and increased movement of macrophages in the blood past the barrier and to the sites of inflammation.
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The researchers then tested the relation of LXRa to blood-brain barrier function in a mouse with experimental autoimmune encephalomyelitis, a mouse model of Multiple Sclerosis. Shut down of the LXRa gene caused the disease to worsen. The levels of white blood cells in the brain and inflammation of blood vessels increased. Additionally, tight junction molecule claudin-5 decreased. These results parallel the results on the in vitro experiment, indicating that the LXRa is crucial to maintaining blood-brain barrier function in neuroinflammatory disorders.
These results suggest that liver X receptors boost the blood-brain barrier’s protective power and are important for slowing the progression of neuroinflammatory diseases. Additionally, the study identified this function belonging to LXRa and not LXRb. This opens up the possibility for therapeutic strategies that increase the activity of LXRa, leading to a more tightly regulated blood brain barrier. Although mouse models of Multiple Sclerosis were the focus of this study, LXR receptors are also being considered in cases of other neuroinflammatory disorders, including Alzheimer’s disease, a neurodegenerative disorder affecting millions of patients each year which causes memory loss, cognitive impairment, and ultimately, death. Like Multiple Sclerosis, Alzheimer’s disease may result from leakage of the blood brain barrier, so targeting LXRa may curtail the progression of this disease as well (1). These details offer hope to Multiple Sclerosis patients and others that tackling the disease may lie in the helping hands of liver X receptors.
(1) Zipser BD, Johanson CE, Gonzalez L, Berzin TM, Tavares R, Hulette CM, Vitek MP, Hovanesian V, Stopa EG (2007) Microvascular injury and blood-brain barrier leakage in Alzheimer’s disease. Neurobiology of Aging. 28:7.
Wouters E, de Wit NM, Vanmol J, van der Pol SMA, van het Hof B, Sommer D, Loix M, Geerts D, Gustafsson JA, Steffensen KR, Vanmierlo T, Bogie JFJ, Hendriks JJA and de Vries HE (2019) Liver X Receptor Alpha Is Important in Maintaining Blood-Brain Barrier Function. Front. Immunol. 10:1811. doi: 10.3389/fimmu.2019.01811