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Innate Immune Reprogramming Mediated by Endogenous Retroelement Dysregulation Drives Multiple Sclerosis Progression
Li-Mei Xiao1,2,3, Qiu-Ping Zhao1,2,3, Run-Yun Li1,3
1Department of Neurology, Fujian Institute of Neurology, the First Affiliated Hospital of Fujian Medical University, Fuzhou, China.
Background:
Skewed myelopoiesis in the bone marrow has been identified as a key driver of multiple sclerosis (MS) progression. Interestingly, SARS-CoV-2 infection, which has a severe impact on MS patients, can also induce similar skewed myelopoiesis. This shared phenotype raises the question of whether a common mechanism underlies the skewed myelopoiesis in both diseases. Previous studies in mice have demonstrated that the dysregulation of endogenous retroelements (EREs) in HSPCs leads to skewed myelopoiesis. Building on this, we sought to determine whether ERE dysregulation contributes to the skewed myelopoiesis observed in MS and after COVID-19, which remains challenging.
Methods:
We undertook a joint investigation of two public single-cell/nuclei cohorts respectively representing MS and following COVID-19. Both cohorts were processed through an identical bioinformatic pipeline to ensure comparable assessment of gene and ERE expression.
Results:
We observed enhanced myelopoiesis in the bone marrow of MS patients compared to healthy controls, along with downregulation of the ERE repressor H3.3 and concomitant EREs overexpression. Notably, a similar epigenetic and transcript feature was found in post-COVID-19 individuals.
Conclusion:
The H3.3low/EREhigh signature may not only explain the common skewed myelopoiesis in MS and post-COVID-19 conditions, but also provide a mechanistic link between infection and the innate immune reprogramming that drives MS progression. This offers a novel therapeutic insight for MS.
Insights
A shared H3.3 low/endogenous retroelements (EREs) high signature in bone marrow myelopoiesis links multiple sclerosis (MS) and post-COVID-19 conditions, offering new therapeutic insights for MS progression.
Area of Science:
- Immunology
- Genetics
- Neurology
Background:
- Skewed myelopoiesis is a key driver of multiple sclerosis (MS) progression.
- SARS-CoV-2 infection can induce myelopoiesis similar to that seen in MS.
- Dysregulation of endogenous retroelements (EREs) in hematopoietic stem and progenitor cells (HSPCs) can cause skewed myelopoiesis.
Purpose of the Study:
- To investigate if ERE dysregulation contributes to skewed myelopoiesis in MS and post-COVID-19.
- To identify common mechanisms underlying skewed myelopoiesis in both conditions.
Main Methods:
- Joint analysis of two public single-cell/nuclei cohorts (MS and post-COVID-19).
- Application of an identical bioinformatic pipeline for gene and ERE expression assessment.
Main Results:
- Enhanced myelopoiesis observed in MS patients compared to controls.
- Downregulation of the ERE repressor H3.3 and overexpression of EREs found in MS.
- Similar epigenetic and transcript features identified in post-COVID-19 individuals.
Conclusions:
- The H3.3 low/ERE high signature may explain common skewed myelopoiesis in MS and post-COVID-19.
- This signature provides a mechanistic link between infection and innate immune reprogramming in MS.
- Offers novel therapeutic insights for MS progression.
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