Shandong University found that Smek1 plays a protective role in demyelinating diseases

A research team led by Professor Liu Qiqi from the School of Basic Medicine of Shandong University recently discovered that Smek1 plays a protective role in demyelinating diseases of the central nervous system
.
The results published in the Journal of Neuroinflammation broaden our understanding of the genetic factors involved in the pathogenesis of demyelination

In recent years, the incidence of demyelinating diseases of the central nervous system has been increasing year by year, which has had a serious impact on the quality of life of patients
.
Clinically common demyelinating diseases include multiple sclerosis and optic neuromyelitis

At present, it is not clear how genetic factors contribute to neuroinflammation in MS and EAE
.
SMEK1 is the regulatory subunit of protein phosphatase 4 (PP4), which can regulate the activity of the catalytic subunit of PP4, leading to the dephosphorylation of its target substrate through an unknown mechanism

Smek1 deficiency causes more severe symptoms in the EAE model

The research team first constructed Smek1 conditional gene knockout mice, called Smek1 ^-/+ mice , with the assistance of Saiye Biology and other institutions
.
In order to study the role of Smek1 in autoimmune demyelination, they used myelin oligodendrocyte glycoprotein 35-55 peptide to establish EAE models in Smek1 ^-/+ mice and wild-type mice, and recorded The clinical symptoms

Smek1 heterozygosity promotes microglia and macrophage activation

The researchers hypothesized that the heterozygosity of Smek1 expression may be sufficient to promote the activation of microglia and mediate neuroinflammation
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Subsequent experiments confirmed this

Later, through single-cell transcriptome analysis, mouse microglia were divided into four groups
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Most wild-type cells are concentrated in clusters 0 and 1, while Smek1 ^-/- cells mainly appear in clusters 2 and 3

Figure 1.
Microglia can be divided into four cell clusters

At the same time, they also discovered a new type of Csf1+ microglia in Cluster 3 (Figure 2).
Csf1 is a key regulator of myeloid lineage cells and supports different subpopulations of microglia
.
Csf1 + microglia in Smek1 ^-/- mice express IL-1β and chemokines at high levels, indicating that in the case of partial or complete loss of Smek1 function, this new cell may have a pre-activated phenotype, resulting in Neuroinflammation

Figure 2.
Csf1+ microglia appear in Smek1-deficient central nervous system

Since microglia are derived from yolk sac macrophages, which can also differentiate into peripheral macrophages, the researchers hypothesized that Smek1 ^-/+ macrophages also cause neuroinflammation
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They found that the ratio of F4/80+ IL-1β+ macrophages in the periphery of the Smek1 hybrid increased, and the fluorescence intensity of macrophages IL-1β in the spleen increased

Smek1 maintains immunosuppressive function by regulating the IDO1-AhR pathway

Since the activation of CD4+ helper T cells in the myelin sheath is critical to the pathogenesis of MS, they next analyzed whether CD4+ T cells are involved in the deterioration of EAE in Smek1 ^-/+ mice
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They found that the IFN-γ secreted by Th1 cells of Smek1 ^-/+ mice was lower than that of control mice, and the expression level of indoleamine 2,3-dioxygenase 1 (IDO1) was also down-regulated
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These results indicate that when Smek1 is partially deleted, Th1 cells down-regulate IFN-γ after activation, and inhibit the expression of IDO1 through the IFN-γ/STAT1 axis
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Previous evidence indicates that IFN-γ plays a beneficial role in EAE, so IFN-γ reduction may be a risk factor for disease development
.

In addition, they also found that reduced IDO1 activity caused AhR nuclear translocation dysfunction and reduced AhR signal in the spinal cord cells of Smek1 ^-/+ EAE mice
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AhR is a positive transcription factor for IL-10, and IL-10 can inhibit inflammation
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After analyzing the IL-10 expression of EAE mice, they found that the clinical score of Smek1 ^-/+ mice was negatively correlated with IL-10 levels, and decreased IL-10 levels were detected in mouse spleen and lymph node Th2 cells
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These results indicate that the down-regulation of the IDO1-AhR pathway destroys the immunosuppression of myeloid cells in Smek1 ^-/+ mice, and is closely related to the worsening of clinical symptoms in Smek1 ^-/+ EAE mice (Figure 3)
.

Figure 3.
Schematic diagram of the pathogenesis of EAE

in conclusion

The author believes that SMEK1 plays a key role in maintaining microglia homeostasis by mediating microglia pre-activation
.
SMEK1 in the peripheral blood mononuclear cells and brain tissues of patients with multiple sclerosis was down-regulated
.
Therefore, the reduction of Smek1 (similar to the heterozygosity of Smek1) may be used as a sensitive background, leading to autoimmune diseases of the central nervous system under the combined action of other genetic or environmental factors
.
Therefore, Smek1 may also be used as a target to develop early intervention treatments for multiple sclerosis
.

Original Search

Duan, RN.
, Yang, CL.
, Du, T.
et al.
Smek1 deficiency exacerbates experimental autoimmune encephalomyelitis by activating proinflammatory microglia and suppressing the IDO1-AhR pathway.
J Neuroinflammation 18, 145 (2021).
https://doi.
org/10.
1186/s12974-021-02193-0