Revealing the molecular mechanism of the "black hole" of multiple sclerosis iron deposition inflammation-lymphocyte-glia immune axis

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Multiple sclerosis (MS) is a chronic central nervous system disease accompanied by focal inflammation-related white matter and gray matter demyelinating lesions
.

After the acute onset of inflammatory demyelination, the chronic phase can present different pathological states: "Chronic active phase (slowly expanding lesion), during this period, the lesion is characterized by slowly increasing volume and continuous tissue loss; chronic Remyelination occurs in the inactive phase
.

According to the part of the chronically active lesion, it can be divided into the core area (significant axon loss area) and the marginal inflammatory area
.

In multiple sclerosis, there is iron accumulation on the edge of chronic demyelinating lesions.
In the activated microglia/macrophages, paramagnetic marginal lesions are formed
.
The more
such paramagnetic marginal lesions plaques, the more likely to have cognitive and dysfunction
.

September 8, 2021 National Institutes of Health National The research team of Daniel S.
Reich of the Institute of Neurological Diseases and Stroke published an article in the journal Nature revealing the molecular mechanism of the paramagnetic marginal disease in the chronic active phase of multiple sclerosis
.

Researchers used single-cell nuclear sequencing technology to analyze the different stages of multiple sclerosis patients Sequencing of the diseased tissues found that 89% of the cells in the white matter around the plaque were oligodendrocytes, and the proportion of immune cells was about 6%; while the proportion of immune cells in the marginal diseased tissue was reduced to about 60%, and astrocytes The proportion of cells is 19%, and the proportion of immune cells has increased to 15%
.

More specifically, the multiple sclerosis inflammatory microglia (MIMS) accounted for about 25% of the immune cell components in the marginal disease tissue, and the monocytes accounted for about 25%.
It accounts for 19%, monocyte-derived and macrophages around blood vessels account for about 8%, and activated T cells account for about 6%
.

There are two types of multiple sclerosis inflammatory microglia (MIMS): one type is mainly involved in myelin phagocytosis and clearance, expressing lipid storage and foam-like cells (specifically targeting the accumulation of cholesterol and fat in blood vessels), differentiation, and lysozyme The cell population of genes related to the somatic signaling pathway; a cell population that directly participates in the inflammatory response and highly expresses the inflammatory cytokine gene IL1B, MHC class II protein complex, and complement C1 complex gene
.

Another type of glial cell population is multiple sclerosis inflammatory astrocytes (AIMS), which are rich in expression of lipids, corticosteroids, and trauma response signaling pathways
.

 Through gene interaction analysis, it is found that in the entire multiple sclerosis-related gene network, MIMS and AIMS form a hub, which is directly connected with other immune cells and glial cell groups
.

In addition, the gene regulation modules of these two glial cell populations are highly correlated, and the complement signaling pathway genes (complement C1q, C3) are enriched and expressed
.

By specifically knocking out complement C1q on microglia, the total number of microglia and the number of activated microglia increased in multiple sclerosis animal models
.

In addition, C1q neutralizing antibodies can effectively reduce the level of C1q in multiple sclerosis animal models and reduce the proportion of activated microglia
.

In summary, this article analyzes the molecular characteristics of paramagnetic borderline inflammatory lesions in multiple sclerosis through single-cell nuclear sequencing technology, and finds that complement C1q is a key molecule that regulates the activation of microglia
.

[References] 1.
https://doi.
org/10.
1038/s41586-021-03892-7 The pictures in the text are from the references