Pharmacological Inhibition of STAT3 by Stattic Ameliorates Clinical Symptoms and Reduces Autoinflammation in Myeloid, Lymphoid, and Neuronal Tissue Compartments in Relapsing–Remitting Model of Experimental Autoimmune Encephalomyelitis in SJL/J Mice

Abstract

Multiple sclerosis (MS) is an immune-mediated inflammatory disease that leads to demyelination and neuronal loss in the central nervous system. Immune cells of lymphoid and myeloid origin play a significant role in the initiation and amplification of neuronal inflammation in MS. STAT3 signaling plays a pivotal role in both myeloid and lymphoid immune cells, such as neutrophils and CD4+ T cells, through regulation of their inflammatory potential. Dysregulation in STAT3 signaling in myeloid and lymphoid cell compartments has been reported in MS. In this report, we attempted to investigate the effect of a small molecular inhibitor of STAT3, i.e., Stattic, in a relapsing–remitting (RR) model of experimental autoimmune encephalomyelitis (EAE). The effect of Stattic was investigated for clinical features, oxidative stress parameters, and Th17-related signaling in both the periphery and brain of SJL/J mice. Our data report that p-STAT3 expression is elevated in granulocytes, CD4+ T cells, and brain tissue in myelin proteolipid protein (PLP)-immunized SJL/J mice, which is associated with the presence of clinical symptoms and upregulation of inflammatory markers in these cells/tissues. Treatment with Stattic leads to the amelioration of disease symptoms and attenuation of inflammatory markers in neutrophils (iNOS/nitrotyrosine/IL-1β), CD4+ T cells (IL-17A/IL-23R), and brain tissue (IL-17A/iNOS/IL-1β/MPO activity/lipid peroxides) in mice with EAE. These data suggest that the blockade of STAT3 signaling in cells of lymphoid and myeloid origin may cause the attenuation of systemic and neuronal inflammation, which could be responsible for the amelioration of disease symptoms in an RR model of EAE. Therefore, pharmacological inhibition of STAT3 in RRMS could be a potential therapeutic strategy.

β-Adrenoceptor Blockade Moderates Neuroinflammation in Male and Female EAE Rats and Abrogates Sexual Dimorphisms in the Major Neuroinflammatory Pathways by Being More Efficient in Males

“…Finally, it is important to underscore that changes in expression/activity of both Stat3 and Socs3 are shown to affect clinical severity of MS/EAE. Pharmacological inhibition of Stat3 (Dang et al 2021;Alhazzani et al 2021) and, more important in respect of our study, the conditional deletion of Stat3 in myeloid cells (Lu et al 2020), have been shown to ameliorate and abrogate symptoms of EAE, respectively. The beneficial effects of these experimental treatments/procedures on EAE development partly or entirely (conditional deletion of Stat3 in myeloid cells) have been ascribed to impaired antigen presentation by myeloid cells and their diminished capacity to drive differentiation of pathogenic Th17 cells.…”

The Shared Mechanism and Candidate Drugs of Multiple Sclerosis and Sjögren’s Syndrome Analyzed by Bioinformatics Based on GWAS and Transcriptome Data

“…Moreover, highly activated STAT3 in T cells of clinically isolated syndrome (CIS) patients can predict the possibility of progression to MS ( 29 ). In addition, elevated STAT3 in brain myeloid cells was observed in MS patients and experimental autoimmune encephalomyelitis (EAE) model, proving its vital contribution to the regulation of myeloid cell function ( 30 , 31 ). Moreover, selective ablation of STAT3 made mice resistant to EAE induction by inhibiting the production of pathogenic T cells ( 31 ).…”

“…In addition, elevated STAT3 in brain myeloid cells was observed in MS patients and experimental autoimmune encephalomyelitis (EAE) model, proving its vital contribution to the regulation of myeloid cell function ( 30 , 31 ). Moreover, selective ablation of STAT3 made mice resistant to EAE induction by inhibiting the production of pathogenic T cells ( 31 ). Immunohistochemical analysis of labial salivary gland (LSG) in SS patients showed that the expression of JAK1 and JAK2 was enhanced in ductal cells and acinar cells, respectively.…”

Treatment with MDL 72527 Ameliorated Clinical Symptoms, Retinal Ganglion Cell Loss, Optic Nerve Inflammation, and Improved Visual Acuity in an Experimental Model of Multiple Sclerosis

“…Further, the activation of STAT3 signaling, a downstream effector of the ERK pathway, is also regulated by MDL 72527 treatment. STAT3 signaling is demonstrated to be a major player in EAE-induced [ 79 ] tissue damage [ 93 , 94 , 95 , 96 , 97 ]. The impact of MDL 72527 indicated in the present study supports the potential of SMOX inhibition in reducing inflammation, in addition to neuroprotection.…”