Abstract
BackgroundAlthough the exact pathophysiology of MS has not been identified, mitochondrial stress can be one of the culprits in MS development. Herein, we have applied microarray analysis, single-cell sequencing analysis, and ex vivo study to elucidate the role of mitochondrial stress in PBMCs of MS patients.MethodsFor this purpose, we analyzed the GSE21942 and GSE138266 datasets to identify the DEGs and hub genes in the PBMCS of MS patients and describe the expression of shared genes in the different immune cells. The GO pathway analysis of DEGs and turquoise module genes were conducted to shed light on their biological significance. To validate the obtained results, the gene expression of HBD, as the most remarkable DEG in the PBMCS of affected patients, was measured in the PBMCS of healthy donors, treatment-naïve MS patients, and MS patients treated with GA, fingolimod, DMF, and IFNβ-1α.ResultsBased on WGCNA and DEGs analysis, HBD, HBM, SLC4A1, LILRA5, SLC25A37, SELENBP1, ALYREF, SNRNP40, and HINT3 are the identified common genes in the PMBCS. Using single-cell sequencing analysis on PBMCS, we have characterized various cell populations in MS and illustrated the common gene expression on the different immune cells. Furthermore, GO pathway analysis of DEGs, and turquoise module genes have indicated that these genes are involved in immune responses, myeloid cell activation, leukocyte activation, oxygen carrier activity, and replication fork processing bicarbonate transport pathways. Our ex vivo investigation has shown that HBD expression in the treatment-naïve RRMS patients is significantly increased compared to healthy donors. Of interest, immunomodulatory therapies with fingolimod, DMF, and IFNβ-1α have significantly decreased HBD expression.ConclusionHBD is one of the remarkably up-regulated genes in the PBMCS of MS patients. HBD is substantially up-regulated in treatment-naïve MS patients, and immunomodulatory therapies with fingolimod, DMF, and IFNβ-1α can remarkably down-regulate HBD expression. Based on the currently available evidence, the cytoprotective nature of HBD against oxidative stress can be the underlying reason for HBD up-regulation in MS. Nevertheless, further investigations are needed to shed light on the molecular mechanisms of HBD in the oxidative stress of MS patients.
Highlights
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) that affects more than 2.5 million people worldwide [1]
We have investigated the expression of Hemoglobin Subunit Delta (HBD), as a gene that has critical roles in oxidative stress, in healthy donors, treatmentnaïve MS patients, and MS patients treated with GA, fingolimod, dimethyl fumarate (DMF), and interferon-beta 1-alpha (IFNb-1a) to validate the results of in-silico analysis
Our analysis has revealed that Hemoglobin Subunit Mu (HBM), SELENBP1, and Solute Carrier Family 4 Member 1 (SLC4A1) are up-regulated in the peripheral blood mononuclear cells (PBMCs) of MS patients; further investigations are needed to be conducted to investigate whether they have roles in the oxidative stress of MS or not
Summary
MS is an inflammatory demyelinating disease of the CNS that affects more than 2.5 million people worldwide [1]. Since epidemiological studies have shown that the relatives of affected individuals are at a higher risk of developing severe MS, genetic factors have been implicated in its pathogenesis [3, 4]. Environmental factors, e.g., latitude, have roles in its pathogenesis [5]. Growing evidence has indicated that mitochondrial oxidative stress plays a pivotal role in the pathogenesis of MS [7]. A better understanding of the mitochondrial stress in PBMCs is needed for developing novel targeted therapy for MS patients. We have applied microarray analysis, single-cell sequencing analysis, and ex vivo study to elucidate the role of mitochondrial stress in PBMCs of MS patients
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