Loss of AMPK exacerbates experimental autoimmune encephalomyelitis disease severity.
AMP-activated protein kinase (AMPK) is an energy sensing metabolic switch in mammalian cells. Here, we report our novel finding that AMPK is lost in all immune cells of experimental autoimmune encephalomyelitis (EAE), an inflammatory disease of Central Nervous System (CNS). AMPKalpha1 is predominantly expressed in T cells and antigen presenting cells (APCs), which are primarily involved in EAE disease progression. AMPK is lost at protein level in spleen macrophages, total T cells and their subsets (CD4, CD8 and regulatory T cells) isolated from EAE afflicted animals compared to control, without affecting its mRNA levels suggesting that the loss of AMPK protein is the result of posttranscriptional modification. To examine its pathological relevance in inflammatory disease, EAE was induced in wild type (+/+) and AMPKalpha1 null mice (-/-) using MOG(35-55) peptide. AMPKalpha1(-/-) mice exhibited severe EAE disease with profound infiltration of mononuclear cells compared to wild type mice however, AMPKalpha2 is not involved in enhancing the severity of the disease. Spleen cells isolated from AMPKalpha1(-/-) immunized mice exhibited a significant induction in the production of IFNgamma. Our study identifies AMPK as a down regulated target during disease in all immune cells and possibly restoring AMPK may serve as a novel therapeutic target in autoimmune diseases like multiple sclerosis (MS).
Nath
Narender
N
Department of Pediatrics, Medical University of South Carolina, SC 29425, USA.
Khan
Musfiquidin
M
Rattan
Ramandeep
R
Mangalam
Ashutosh
A
Makkar
Randhir S
RS
de Meester
Carloe
C
Bertrand
Luc
L
Singh
Inderjit
I
Chen
Yingjie
Y
Viollet
Benoit
B
Giri
Shailendra
S
D055372:AMP-Activated Protein Kinases / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D015536:Down-Regulation; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000201:enzymology* / Q000473:pathology*; D007527:Isoenzymes / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D021122:Protein Subunits / Q000096:biosynthesis / Q000235:genetics; D013154:Spleen / Q000201:enzymology
D007527:Isoenzymes; D021122:Protein Subunits; D055372:AMP-Activated Protein Kinases