Severity of the autoimmune encephalomyelitis symptoms in mouse model by inhibition of LAT-1 transporters
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ORIGINAL ARTICLE
Severity of the autoimmune encephalomyelitis symptoms in mouse model by inhibition of LAT‑1 transporters Khandoker Asiqur Rahaman1,3 · Mahbub Hasan1 · Ji‑Eun Seo1 · Anca Raluca Muresan1,3 · Hye Jin Song1 · Hophil Min1 · Junghyun Son1 · Jaeick Lee1 · Joonhee Lee2 · Byungjoo Kim2 · Oh‑Seung Kwon1,3 Received: 22 October 2019 / Accepted: 4 December 2019 © The Korean Society of Pharmaceutical Sciences and Technology 2019
Abstract 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 LAT1-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. Keywords LAT-1 transporter · Leucine · T Cells · Experimental autoimmune encephalomyelitis · BCH
Introduction Multiple sclerosis (MS) is a disease of misguided immune cells that are stimulated by self-myelin proteins and cross the blood–brain barrier into the central nervous system (CNS).
* Oh‑Seung Kwon [email protected] 1
Doping Control Center, Korea Institute of Science and Technology, Hwarangno 14‑gil 5, Seongbuk‑gu, Seoul 02792, Republic of Korea
2
Center for Organic Analysis, Division of Metrology for Quality Life, Korea Research Institute of Standards and Science, 267 Gajeong‑ro, Yuseong‑gu, Daejeon 34113, Korea
3
Division of Bio‑Medical Science & Technology, KIST School, Korea University of Science and Technology, Seoul 02792, Korea
The immune cells cause damage to the myelin sheath by the simultaneous triggering of cytokines and cytotoxic T cells. Experimental autoimmune encephalomyelitis (EAE) is an autoimm
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