Downregulation of LKB1/AMPK Signaling in Blood Mononuclear Cells Is Associated with the Severity of Guillain–Barre Syndrome
AMP-activated protein kinase (AMPK) is an intracellular energy sensor that regulates metabolic and immune functions mainly through the inhibition of the mechanistic target of rapamycin (mTOR)-dependent anabolic pathways and the activation of catabolic processes such as autophagy. The AMPK/mTOR signa...
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MDPI AG
2022-09-01
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| Online Access: | https://www.mdpi.com/2073-4409/11/18/2897 |
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| author | Verica Paunovic Stojan Peric Irena Vukovic Marina Stamenkovic Emina Milosevic Danijela Stevanovic Milos Mandic Ivana Basta Ivana Berisavac Mirjana Arsenijevic Ivo Bozovic Marko Nikolic Zorica Stevic Vladimir Trajkovic |
| author_facet | Verica Paunovic Stojan Peric Irena Vukovic Marina Stamenkovic Emina Milosevic Danijela Stevanovic Milos Mandic Ivana Basta Ivana Berisavac Mirjana Arsenijevic Ivo Bozovic Marko Nikolic Zorica Stevic Vladimir Trajkovic |
| author_sort | Verica Paunovic |
| collection | DOAJ |
| description | AMP-activated protein kinase (AMPK) is an intracellular energy sensor that regulates metabolic and immune functions mainly through the inhibition of the mechanistic target of rapamycin (mTOR)-dependent anabolic pathways and the activation of catabolic processes such as autophagy. The AMPK/mTOR signaling pathway and autophagy markers were analyzed by immunoblotting in blood mononuclear cells of 20 healthy control subjects and 23 patients with an acute demyelinating form of Guillain–Barré syndrome (GBS). The activation of the liver kinase B1 (LKB1)/AMPK/Raptor signaling axis was significantly reduced in GBS compared to control subjects. In contrast, the phosphorylated forms of mTOR activator AKT and mTOR substrate 4EBP1, as well as the levels of autophagy markers LC3-II, beclin-1, ATG5, p62/sequestosome 1, and NBR1 were similar between the two groups. The downregulation of LKB1/AMPK signaling, but not the activation status of the AKT/mTOR/4EBP1 pathway or the levels of autophagy markers, correlated with higher clinical activity and worse outcomes of GBS. A retrospective study in a diabetic cohort of GBS patients demonstrated that treatment with AMPK activator metformin was associated with milder GBS compared to insulin/sulphonylurea therapy. In conclusion, the impairment of the LKB1/AMPK pathway might contribute to the development/progression of GBS, thus representing a potential therapeutic target in this immune-mediated peripheral polyneuropathy. |
| first_indexed | 2024-03-10T00:25:43Z |
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| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T00:25:43Z |
| publishDate | 2022-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-6afd242513c742088b5f9df72be131082023-11-23T15:34:02ZengMDPI AGCells2073-44092022-09-011118289710.3390/cells11182897Downregulation of LKB1/AMPK Signaling in Blood Mononuclear Cells Is Associated with the Severity of Guillain–Barre SyndromeVerica Paunovic0Stojan Peric1Irena Vukovic2Marina Stamenkovic3Emina Milosevic4Danijela Stevanovic5Milos Mandic6Ivana Basta7Ivana Berisavac8Mirjana Arsenijevic9Ivo Bozovic10Marko Nikolic11Zorica Stevic12Vladimir Trajkovic13Institute of Microbiology and Immunology, Faculty of Medicine, University of Belgrade, Dr. Subotica 1, 11000 Belgrade, SerbiaNeurology Clinic, University Clinical Center of Serbia, Faculty of Medicine, University of Belgrade, Dr. Subotica 6, 11000 Belgrade, SerbiaInstitute of Microbiology and Immunology, Faculty of Medicine, University of Belgrade, Dr. Subotica 1, 11000 Belgrade, SerbiaInstitute of Microbiology and Immunology, Faculty of Medicine, University of Belgrade, Dr. Subotica 1, 11000 Belgrade, SerbiaInstitute of Microbiology and Immunology, Faculty of Medicine, University of Belgrade, Dr. Subotica 1, 11000 Belgrade, SerbiaInstitute of Microbiology and Immunology, Faculty of Medicine, University of Belgrade, Dr. Subotica 1, 11000 Belgrade, SerbiaInstitute of Microbiology and Immunology, Faculty of Medicine, University of Belgrade, Dr. Subotica 1, 11000 Belgrade, SerbiaNeurology Clinic, University Clinical Center of Serbia, Faculty of Medicine, University of Belgrade, Dr. Subotica 6, 11000 Belgrade, SerbiaNeurology Clinic, University Clinical Center of Serbia, Faculty of Medicine, University of Belgrade, Dr. Subotica 6, 11000 Belgrade, SerbiaNeurology Clinic, University Clinical Center of Serbia, Faculty of Medicine, University of Belgrade, Dr. Subotica 6, 11000 Belgrade, SerbiaNeurology Clinic, University Clinical Center of Serbia, Faculty of Medicine, University of Belgrade, Dr. Subotica 6, 11000 Belgrade, SerbiaNeurology Clinic, University Clinical Center of Serbia, Faculty of Medicine, University of Belgrade, Dr. Subotica 6, 11000 Belgrade, SerbiaNeurology Clinic, University Clinical Center of Serbia, Faculty of Medicine, University of Belgrade, Dr. Subotica 6, 11000 Belgrade, SerbiaInstitute of Microbiology and Immunology, Faculty of Medicine, University of Belgrade, Dr. Subotica 1, 11000 Belgrade, SerbiaAMP-activated protein kinase (AMPK) is an intracellular energy sensor that regulates metabolic and immune functions mainly through the inhibition of the mechanistic target of rapamycin (mTOR)-dependent anabolic pathways and the activation of catabolic processes such as autophagy. The AMPK/mTOR signaling pathway and autophagy markers were analyzed by immunoblotting in blood mononuclear cells of 20 healthy control subjects and 23 patients with an acute demyelinating form of Guillain–Barré syndrome (GBS). The activation of the liver kinase B1 (LKB1)/AMPK/Raptor signaling axis was significantly reduced in GBS compared to control subjects. In contrast, the phosphorylated forms of mTOR activator AKT and mTOR substrate 4EBP1, as well as the levels of autophagy markers LC3-II, beclin-1, ATG5, p62/sequestosome 1, and NBR1 were similar between the two groups. The downregulation of LKB1/AMPK signaling, but not the activation status of the AKT/mTOR/4EBP1 pathway or the levels of autophagy markers, correlated with higher clinical activity and worse outcomes of GBS. A retrospective study in a diabetic cohort of GBS patients demonstrated that treatment with AMPK activator metformin was associated with milder GBS compared to insulin/sulphonylurea therapy. In conclusion, the impairment of the LKB1/AMPK pathway might contribute to the development/progression of GBS, thus representing a potential therapeutic target in this immune-mediated peripheral polyneuropathy.https://www.mdpi.com/2073-4409/11/18/2897Guillain–Barré syndromeperipheral blood mononuclear cellsAMP-activated protein kinaseautophagymTORmetformin |
| spellingShingle | Verica Paunovic Stojan Peric Irena Vukovic Marina Stamenkovic Emina Milosevic Danijela Stevanovic Milos Mandic Ivana Basta Ivana Berisavac Mirjana Arsenijevic Ivo Bozovic Marko Nikolic Zorica Stevic Vladimir Trajkovic Downregulation of LKB1/AMPK Signaling in Blood Mononuclear Cells Is Associated with the Severity of Guillain–Barre Syndrome Cells Guillain–Barré syndrome peripheral blood mononuclear cells AMP-activated protein kinase autophagy mTOR metformin |
| title | Downregulation of LKB1/AMPK Signaling in Blood Mononuclear Cells Is Associated with the Severity of Guillain–Barre Syndrome |
| title_full | Downregulation of LKB1/AMPK Signaling in Blood Mononuclear Cells Is Associated with the Severity of Guillain–Barre Syndrome |
| title_fullStr | Downregulation of LKB1/AMPK Signaling in Blood Mononuclear Cells Is Associated with the Severity of Guillain–Barre Syndrome |
| title_full_unstemmed | Downregulation of LKB1/AMPK Signaling in Blood Mononuclear Cells Is Associated with the Severity of Guillain–Barre Syndrome |
| title_short | Downregulation of LKB1/AMPK Signaling in Blood Mononuclear Cells Is Associated with the Severity of Guillain–Barre Syndrome |
| title_sort | downregulation of lkb1 ampk signaling in blood mononuclear cells is associated with the severity of guillain barre syndrome |
| topic | Guillain–Barré syndrome peripheral blood mononuclear cells AMP-activated protein kinase autophagy mTOR metformin |
| url | https://www.mdpi.com/2073-4409/11/18/2897 |
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