UCP2 up-regulation within the course of autoimmune encephalomyelitis correlates with T-lymphocyte activation

Abstract

Multiple sclerosis (MS) is an inflammatory demyelinating autoimmune disorder of the central nervous system (CNS) associated with severe neurological disability. Reactive oxygen species (ROS) and mitochondrial dysfunction play a pivotal role in the pathogenesis of this disease. Several members of the mitochondrial uncoupling protein subfamily (UCP2-UCP5) were suggested to regulate ROS by diminishing the mitochondrial membrane potential and constitute therefore a promising pharmacological target for MS. To evaluate the role of different uncoupling proteins in neuroinflammation, we have investigated their expression patterns in murine brain and spinal cord (SC) during different stages of experimental autoimmune encephalomyelitis (EAE), an animal model for MS. At mRNA and protein levels we found that only UCP2 is up-regulated in the SC, but not in brain. The increase in UCP2 expression was antigen-independent, reached its maximum between 14 and 21days in both OVA and MOG immunized animals and correlated with an augmented number of CD3 T-lymphocytes in SC parenchyma. The decrease in abundance of UCP4 was due to neuronal injury and was only detected in CNS of MOG-induced EAE animals. The results provide evidence that the involvement of mitochondrial UCP2 in CNS inflammation during EAE may be mainly explained by the invasion of activated T-lymphocytes. This conclusion coincides with our previous observation that UCP2 is up-regulated in activated and rapidly proliferating T-cells and participates in fast metabolic re-programming of cells during proliferation.

Important Trends in UCP3 Investigation

“…UCP5 expression seems to be below the detection level of western blot sensitivity. Furthermore, the ratio of UCP5 mRNA to the housekeeping gene GAPDH is very low compared to UCP2/GAPDH or UCP4/GAPDH (Rupprecht et al, 2014; Smorodchenko et al, 2017).…”

“…This cell and tissue distribution is further supported by several studies using validated UCP2 antibodies (Pecqueur et al, 2001, 2009; Yu et al, 2013). In contrast, UCP4 protein is abundant in highly active cells with low proliferation potential that rely on a stable supply of glucose, such as neurons and neurosensory cells (Mao et al, 1999; Liu et al, 2006; Smorodchenko et al, 2009, 2011, 2017; Rupprecht et al, 2014).…”

“…Because the preferred metabolism of most cells and tissues depends on many physiological conditions that may change under pathological conditions, this concept may partly explain controversial reports concerning UCP expression, particularly for UCP2 in brain, heart, etc. During inflammation or allergic reaction, activated lymphocytes or mast cells massively invade the affected organ, potentially yielding false positive results for expression of UCP2 in inflamed organs (Smorodchenko et al, 2017). It was shown that UCP2 is highly abundant in embryonic heart and during early stages of heart development, coinciding with the glycolytic type of cardiomyocyte metabolism (Hilse et al, 2018).…”

Mitochondrial Uncoupling Proteins: Subtle Regulators of Cellular Redox SignalingReviewing Editors:Jerzy Beltowski, Joseph Burgoyne, Gabor Csanyi, Sergey Dikalov, Frank Krause, Anibal Vercesi, and Jeremy Ward

“…Involvement of UCPs in neurodegenerations such as multiple sclerosis has also been investigated. During the development of autoimmune encephalomyelitis, UCP2 is upregulated in spinal cord and this correlates with activation of proper T-lymphocytes ( 381 ). Thus, T cell UCP2 is upregulated during neuroinflammation.…”

The emerging role of immune dysfunction in mitochondrial diseases as a paradigm for understanding immunometabolism

“…Knockdown of Ucp2 leads to reduced glycolysis, fatty acid synthesis, ROS production, and survival during CD8 + T cell in vitro activation [118]. During experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis, UCP2 was found to be upregulated in T lymphocytes recruited to the spinal cord during periods of neuroinflammation [119]. Whether Ucp2 expression exacerbates autoimmune disease or helps fight infection likely depends on the role of ROS in dealing with specific pathogens or pathological condition.…”