Smek1 deficiency exacerbates experimental autoimmune encephalomyelitis by activating proinflammatory microglia and suppressing the IDO1-AhR pathway

Abstract

Background Experimental autoimmune encephalomyelitis (EAE) is an animal disease model of multiple sclerosis (MS) that involves the immune system and central nervous system (CNS). However, it is unclear how genetic predispositions promote neuroinflammation in MS and EAE. Here, we investigated how partial loss-of-function of suppressor of MEK1 (SMEK1), a regulatory subunit of protein phosphatase 4, facilitates the onset of MS and EAE. Methods C57BL/6 mice were immunized with myelin oligodendrocyte glycoprotein 35-55 (MOG35-55) to establish the EAE model. Clinical signs were recorded and pathogenesis was investigated after immunization. CNS tissues were analyzed by immunostaining, quantitative polymerase chain reaction (qPCR), western blot analysis, and enzyme-linked immunosorbent assay (ELISA). Single-cell analysis was carried out in the cortices and hippocampus. Splenic and lymph node cells were evaluated with flow cytometry, qPCR, and western blot analysis. Results Here, we showed that partial Smek1 deficiency caused more severe symptoms in the EAE model than in controls by activating myeloid cells and that Smek1 was required for maintaining immunosuppressive function by modulating the indoleamine 2,3-dioxygenase (IDO1)-aryl hydrocarbon receptor (AhR) pathway. Single-cell sequencing and an in vitro study showed that Smek1-deficient microglia and macrophages were preactivated at steady state. After MOG35-55 immunization, microglia and macrophages underwent hyperactivation and produced increased IL-1β in Smek1-/+ mice at the peak stage. Moreover, dysfunction of the IDO1-AhR pathway resulted from the reduction of interferon γ (IFN-γ), enhanced antigen presentation ability, and inhibition of anti-inflammatory processes in Smek1-/+ EAE mice. Conclusions The present study suggests a protective role of Smek1 in autoimmune demyelination pathogenesis via immune suppression and inflammation regulation in both the immune system and the central nervous system. Our findings provide an instructive basis for the roles of Smek1 in EAE and broaden the understanding of the genetic factors involved in the pathogenesis of autoimmune demyelination.

Bibliometric and visual analysis of single-cell sequencing from 2010 to 2022

“…For instance, a study on Parkinson’s disease used single-cell RNA sequencing to reveal the molecular signatures and abnormally expressed genes of dopaminergic neurons ( Smajic et al, 2022 ). Based on single-cell sequencing of dopaminergic neurons in a population of PD patients and healthy controls, the investigators identified disease-related genes that were abnormally expressed, which provided important clues for understanding the pathogenesis of PD and identifying new treatments ( Duan et al, 2021 ). Moreover, SCS has provided deeper insights into nervous system functions and disease mechanisms.…”

The triglyceride catabolism regulated by a serine/threonine protein phosphatase, Smek1, is required for development and plant infection in Magnaporthe oryzae

“…In eukaryotes, Smek1 (Psy2) is a conserved regulatory subunit of the protein phosphatase 4 (PP4; Gingras et al, 2005). Smek1 plays diverse roles in organisms, such as DNA repair in Saccharomyces cerevisiae and Candida albicans (Feng et al, 2017; O'Neill et al, 2004), chemotaxis in Dictyostelium (Mendoza Michelle et al, 2005), immune suppression and inflammation regulation (Duan et al, 2021), and neuronal differentiation in mammals (Chang et al, 2017), aging in Caenorhabditis elegans (Sen et al, 2020), miRNA biogenesis in Arabidopsis thaliana (Su et al, 2017), and regulation of glucose homeostasis in mammals and S. cerevisiae (Ma et al, 2014; Yoon et al, 2010). Although the functions of various phosphatases have been reported, phosphatases in signalling pathways that regulate triglyceride catabolism have not been well documented in M. oryzae and other eukaryotes.…”

Microglial aryl hydrocarbon receptor enhances phagocytic function via SYK and promotes remyelination in the cuprizone mouse model of demyelination

“…Recent studies have shown that AhR endogenous agonist levels are significantly lower in MS patients compared to healthy controls and lower AhR agonist levels are correlated with neurological dysfunction and disease severity [ 21 , 22 ], implying that AhR may play an essential role in the pathogenesis of MS. In experimental autoimmune encephalitis (EAE), an animal model of MS, administering agonists to activate AhR suppresses disease progression [ 20 , 23 , 24 ], whereas inhibiting AhR and its immunosuppressive function promotes immune responses and exacerbates EAE [ 25 ]. Moreover, microglial AhR modulates the pathogenic activity of astrocytes and CNS inflammation in the EAE model [ 26 ].…”