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KMID : 1146920200500050481
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Journal of Pharmaceutical Investigation
2020 Volume.50 No. 5 p.481 ~ p.491
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Severity of the autoimmune encephalomyelitis symptoms in mouse model by inhibition of LAT-1 transporters
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Rahaman Khandoker Asiqur
Hasan Mahbub
Seo Ji-Eun
Muresan Anca Raluca
Song Hye-Jin
Min Ho-Phil
Son Jung-Hyun
Lee Jae-Ick
Lee Joon-Hee
Kim Byung-Joo
Kwon Oh-Seung
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Abstract
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Purpose: Experimental autoimmune encephalomyelitis (EAE) is an autoimmune disease of the dynamic immune system acting against the myelin sheath of neuronal axons in the abluminal (brain-facing) side of the central nervous system. This immune system is greatly influenced by the free amino acid environment from the luminal (blood-facing) side. Whether the luminal and abluminal free amino acid balance influences EAE disease progression is still unclear.
Methods: Changes in free amino acid levels on both sides of the blood?brain barrier were observed with or without blocking of the L-amino acid transporter (LAT-1) during EAE disease progression. Brain tissue, plasma, splenocytes samples were used to measure free amino acid by LC?MS/MS. Samples were also used to measure cytokines by ELISA and numbers of immune cells by flow cytometry.
Results: In the chronic stage of EAE progression, clinical scores of LAT-1-inhibited EAE mice were higher than those of normal EAE mice. Significantly elevated T-cell counts, MMP-9 activity, and IL-6 levels were found in the LAT-1-inhibited EAE group. Inhibition of LAT-1 with 2-amino-2-norbornanecarboxylic acid (BCH) treatment resulted in decreased leucine concentration in splenocytes and increased leucine levels in plasma. The leucine levels on the abluminal side of LAT-1-inhibited EAE mice were also significantly higher than those of control mice but not those of EAE mice.
Conclusion: The increased leucine concentration present at the luminal side crossed the blood brain barrier (BBB) and fueled inflammation with concurrent disease severity in the abluminal side of EAE mice.
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KEYWORD
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LAT-1 transporter, Leucine, T Cells, Experimental autoimmune encephalomyelitis, BCH
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