Biological Aging of CNS-Resident Cells Alters the Clinical Course and Immunopathology of Autoimmune Demyelinating Disease
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ABSTRACT:
PROVIDER: PRJNA827157 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR18776408_1.fastq.gz | Fastqsanger.gz | |||
| SRR18776408_2.fastq.gz | Fastqsanger.gz | |||
| SRR18776409_1.fastq.gz | Fastqsanger.gz | |||
| SRR18776409_2.fastq.gz | Fastqsanger.gz | |||
| SRR18776410_1.fastq.gz | Fastqsanger.gz |
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Project description:Biological aging is the strongest factor associated with the clinical phenotype of multiple sclerosis (MS). Relapsing-remitting MS typically presents in the third or fourth decade, whereas the mean age of presentation of progressive MS (PMS) is 45 years old. Here, we show that experimental autoimmune encephalomyelitis (EAE), induced by the adoptive transfer of encephalitogenic CD4+ Th17 cells, was more severe, and less likely to remit, in middle-aged compared with young adult mice. Donor T cells and neutrophils were more abundant, while B cells were relatively sparse, in CNS infiltrates of the older mice. Experiments with reciprocal bone marrow chimeras demonstrated that radio-resistant, nonhematopoietic cells played a dominant role in shaping age-dependent features of the neuroinflammatory response, as well as the clinical course, during EAE. Reminiscent of PMS, EAE in middle-aged adoptive transfer recipients was characterized by widespread microglial activation. Microglia from older mice expressed a distinctive transcriptomic profile suggestive of enhanced chemokine synthesis and antigen presentation. Collectively, our findings suggest that drugs that suppress microglial activation, and acquisition or expression of aging-associated properties, may be beneficial in the treatment of progressive forms of inflammatory demyelinating disease.
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Project description:Theiler’s murine encephalomyelitis virus (TMEV) induces different diseases in the central nervous system (CNS) and heart, depending on the mouse strains and time course, where cytokines play a key role for viral clearance and immune-mediated pathology (immunopathology). In SJL/J mice, TMEV infection causes chronic TMEV-induced demyelinating disease (TMEV-IDD) in the spinal cord around 1 month post infection (p.i.). Unlike other immunopathology models, both pro-inflammatory and anti-inflammatory cytokines can play dual roles in TMEV-IDD. Pro-inflammatory cytokines play a beneficial role in viral clearance while they also play a detrimental role in immune-mediated demyelination. Anti-inflammatory cytokines suppress not only protective anti-viral immune responses but also detrimental autoreactive immune responses. On the other hand, in C3H mice, TMEV infection induces a non-CNS disease, myocarditis, with three phases: phase I, viral pathology with interferon and chemokine responses; phase II, immunopathology mediated by acquired immune responses; and phase III, cardiac fibrosis. Although the precise mechanism how a single virus, TMEV, induces the distinct diseases in different organs is unclear, principal component analysis (PCA) of transcriptome data allows us to identify the key factors contributing to distinct immunopathology. The PCA demonstrated that in vitro infection of a cardiomyocyte cell line could reproduce the transcriptome profile of phase I in TMEV-induced myocarditis; distinct interferon/chemokine-related responses were induced in vitro in infected cardiomyocytes, but not in infected neuronal cells. In addition, the PCA of in vivo CNS transcriptome data showed that decreased lymphatic marker expression was associated with inflammation in TMEV infection. Here, dysfunction of lymphatic vessels may contribute to immunopathology by delaying clearance of cytokines and immune cells from the inflammatory site, although this might confine the virus at the site, preventing virus spread via lymphatic vessels. On the other hand, in the heart, dysfunction of lymphatics was associated with reduced lymphatic muscle contractility by pro-inflammatory cytokines. Therefore, TMEV infection could induce different cytokine expressions as well as lymphatic vessel dysfunction by the distinct mechanism between the CNS and heart, which might contribute to organ-specific immunopathology.
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