SIRT1 is decreased during relapses in patients with multiple sclerosis
Introduction
Multiple sclerosis (MS) is a demyelinating disease characterized by chronic inflammation of the central nervous system in which many factors (genetic and environmental) may act together to influence disease susceptibility and progression (Frohman et al., 2006, Keegan and Noseworthy, 2002). While a large body of work has enhanced our understanding of the fundamental nature of MS, basic research into its etiology, pathophysiology, and treatment faces enormous challenges, and this may in part be due to the great variability in the clinical presentation and course of MS (Compston and Coles, 2008, Frohman et al., 2006, Keegan and Noseworthy, 2002).
Epigenetic regulators such as histone deacetylases (HDACs) and histone acetyltransferases are increasingly being implicated as direct or indirect components of the regulation of expression of neuronal, immune, and other tissue-specific genes (Koch et al., 2013a, Wang et al., 2013). Post-translational modifications of histone proteins have the ability to affect chromatin structure and regulate gene expression (Koch et al., 2013b, Sengupta and Seto, 2004). Recently, the HDAC inhibitor trichostatin A (TSA) was shown to ameliorate the disease course in experimental autoimmune encephalomyelitis (EAE). Using microarrays and real time-PCR to assess in vivo spinal cord gene regulation by this HDAC inhibitor, multiple genes were found to be up-regulated by TSA in the spinal cords of EAE mice, including anti-oxidant, neuroprotective, and neuronal differentiation genes (Camelo et al., 2005). In addition, the effect of sirtuin 1 (SIRT1) on EAE has recently been investigated (Nimmagadda et al., 2013). SIRT1 is a member of the HDAC class III family of proteins (Smith et al., 2000). It is an NAD+-dependent histone and protein deacetylase (Penberthy and Tsunoda, 2009, Smith et al., 2000) that catalyzes the removal of acetyl groups from a variety of protein substrates (Turner, 1998), including histones H1, H3, and H4 (Turner, 1998, Wang et al., 2011, Zhang and Kraus, 2010). In addition, SIRT1 has been found to promote histone H3K9 methylation, resulting in epigenetic gene silencing (Imai et al., 2000, Vaquero et al., 2004, Vaquero et al., 2007). SIRT1 is involved in the regulation of a number of cellular processes, including transcription, metabolism (Chen et al., 2008, He et al., 2012), DNA repair, and aging (Guarente, 2011). SIRT1 can induce chromatin silencing through the deacetylation of histones (Baur, 2010) and can modulate cell survival by regulating the transcriptional activities of p53 (Luo et al., 2000), NF-κB (Yeung et al., 2004), FOXO proteins (Brunet et al., 2004, Motta et al., 2004), and p300 (Bouras et al., 2005). Recently, resveratrol, a SIRT1 activator, was shown to ameliorate the disease course in experimental autoimmune encephalomyelitis (EAE), an animal model of MS (Fonseca-Kelly et al., 2012, Imler and Petro, 2009, Petro, 2011). Studies have shown the ability of resveratrol to trigger apoptosis in activated T cells and also to induce a decrease in spinal cord inflammation during EAE (Singh et al., 2007). Another study has demonstrated that resveratrol has immunomodulatory effects, altering the percentage of IL-17-positive T cells in the periphery and central nervous system (CNS) following long-term treatment in the relapsing–remitting EAE model (Imler and Petro, 2009). In addition, resveratrol was found to be neuroprotective (Shindler et al., 2010), and the mechanism for its immunomodulatory and neuroprotective effects involved the activation of SIRT1 (Nimmagadda et al., 2013). Little is known about the changes that occur in SIRT1 expression or in the acetylation and methylation of histones in the PBMC and T cells from MS patients. In addition, the expression of SIRT1 in MS patients has not been investigated.
In the present study, we investigated the expression of SIRT1 and HDAC3 in MS patients and compared them to the expression in healthy controls. SIRT1 was found to be expressed in MS brains by inflammatory cells, OLG, and astrocytes. We also found that SIRT1 levels were significantly reduced in MS patients with relapses as compared to control patients. In addition, an increase in histone H3K9 acetylation was found during relapses in MS patients. We also found that SIRT1 levels in PBMCs were significantly decreased after RGC-32 silencing and that SIRT1 also regulated FasL expression and apoptosis. Decreased expression of SIRT1 in PBMCs during relapses and might represent a marker of disease activity in patients with MS.
Section snippets
Brain tissue
Frozen brain tissue specimens acquired at autopsy from six patients with a definitive diagnosis of MS were obtained from the Human Brain and Spinal Fluid Resource Center, Veterans Affairs West Los Angeles Health Care Center. Active lesions contained abundant infiltrates consisting of T cells and macrophages, with detectable myelin degradation products. Inflammation was restricted to the lesion margins in chronic active lesions. Regions of normal-appearing white matter (NAWM) and
Immunohistochemical localization of SIRT1 and HDAC3 in MS brain
Since effector T cells migrate into the brain at the time of an MS relapse (Costantino et al., 2008, Martinez-Pasamar et al., 2013), we investigated the expression of SIRT1 in MS brains in relation to that of T cells and macrophages. We first examined the localization of SIRT1 in 20 areas from 8 patients with MS (Table 2). MS brain samples from active lesions contained abundant inflammatory cell infiltrates, consisting of CD4+ and CD8+ T cells as well macrophages. Acute active lesions contained
Discussion
The aim of our study was to evaluate the expression of SIRT1 and the role it plays in MS. Using immunohistochemical staining, we were able to show that inflammatory cells (T cells and macrophages), OLG, and astrocytes all express SIRT1 in the MS brain. The expression of SIRT1 was not confined to the MS plaques but was also present in NAWM and NAGM areas, indicating a widespread distribution of cells expressing SIRT1. It is important to note that most of the OLGs in the MS brain expressed SIRT1,
Conflict of interest
The authors declare that there are no conflict of interest.
Acknowledgments
We thank Dr. Deborah McClellan for editing this manuscript. This work was supported in part by a Pilot Project PP 1422 from the MS Society (to H.R.) and a Veterans Administration Merit Award (to H.R.). The MS brain samples were obtained from the National Neurological Research Specimen Bank (West Los Angeles Veterans Administration Hospital, Los Angeles, CA).
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2020, Advances in ImmunologyCitation Excerpt :SIRT1 levels in plasma samples from MS patients were shown to be increased compared to healthy controls (Pennisi et al., 2011). However, SIRT1 expression is decreased in PBMCs of MS patients in relapsing disease stages (Ciriello et al., 2018; Hewes et al., 2017; Tegla et al., 2014), while in acute and chronic lesion elevated expression of SIRT1 which colocalizes with inflammatory cells, oligodendrocytes and astrocytes, is observed (Tegla et al., 2014). An additional class III HDAC involved in MS pathogenesis is SIRT2, where a loss of the expression of two SIRT2 isoforms in human MS lesions has been observed (Jastorff et al., 2009).