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Primary Cultures of Rat Astrocytes and Microglia and Their Use in the Study of Amyotrophic Lateral Sclerosis
Published on: June 23, 2022
Dysregulated microRNAs in amyotrophic lateral sclerosis microglia modulate genes linked to neuroinflammation
C Parisi1, I Arisi2, N D'Ambrosi1
11] Cellular Biology and Neurobiology Institute, CNR, Via del Fosso di Fiorano 64, 00143 Rome, Italy [2] Santa Lucia Foundation, Via del Fosso di Fiorano 64, 00143 Rome, Italy.
Abstract:
MicroRNAs (miRNAs) regulate gene expression at post-transcriptional level and are key modulators of immune system, whose dysfunction contributes to the progression of neuroinflammatory diseaseas such as amyotrophic lateral sclerosis (ALS), the most widespread motor neuron disorder. ALS is a non-cell-autonomous disease targeting motor neurons and neighboring glia, with microgliosis directly contributing to neurodegeneration. As limited information exists on miRNAs dysregulations in ALS, we examined this topic in primary microglia from superoxide dismutase 1-G93A mouse model. We compared miRNAs transcriptional profiling of non-transgenic and ALS microglia in resting conditions and after inflammatory activation by P2X7 receptor agonist. We identified upregulation of selected immune-enriched miRNAs, recognizing miR-22, miR-155, miR-125b and miR-146b among the most highly modulated. We proved that miR-365 and miR-125b interfere, respectively, with the interleukin-6 and STAT3 pathway determining increased tumor necrosis factor alpha (TNFα) transcription. As TNFα directly upregulated miR-125b, and inhibitors of miR-365/miR-125b reduced TNFα transcription, we recognized the induction of miR-365 and miR-125b as a vicious gateway culminating in abnormal TNFα release. These results strengthen the impact of miRNAs in modulating inflammatory genes linked to ALS and identify specific miRNAs as pathogenetic mechanisms in the disease.
Insights
MicroRNAs (miRNAs) are crucial in regulating the immune system and are implicated in neuroinflammatory diseases like amyotrophic lateral sclerosis (ALS). This study identifies specific miRNAs that contribute to abnormal tumor necrosis factor alpha (TNFα) release in ALS.
Area of Science:
- Neuroscience
- Immunology
- Molecular Biology
Background:
- MicroRNAs (miRNAs) are key regulators of gene expression and immune function.
- Dysfunctional miRNAs contribute to neuroinflammatory diseases, including amyotrophic lateral sclerosis (ALS).
- ALS is a complex motor neuron disorder involving neuroinflammation and microgliosis.
Purpose of the Study:
- To investigate miRNA dysregulation in primary microglia from an ALS mouse model.
- To identify specific miRNAs involved in the inflammatory response in ALS.
- To elucidate the role of miRNAs in the aberrant release of inflammatory cytokines like TNFα in ALS.
Main Methods:
- Transcriptional profiling of miRNAs in primary microglia from non-transgenic and SOD1-G93A ALS mice.
- Comparison of miRNA expression in resting and P2X7 receptor-activated microglia.
- Functional analysis of specific miRNAs (miR-365, miR-125b) and their impact on inflammatory pathways (IL-6, STAT3, TNFα).
Main Results:
- Upregulation of immune-enriched miRNAs, including miR-22, miR-155, miR-125b, and miR-146b, was identified in ALS microglia.
- miR-365 and miR-125b were shown to modulate the IL-6 and STAT3 pathways, respectively, leading to increased TNFα transcription.
- A positive feedback loop was observed where TNFα upregulated miR-125b, suggesting a self-perpetuating cycle of inflammation.
Conclusions:
- miRNAs significantly impact inflammatory gene modulation in ALS.
- Specific miRNAs, particularly miR-365 and miR-125b, act as pathogenic mechanisms driving abnormal TNFα release in ALS.
- Targeting these miRNAs could offer a therapeutic strategy for managing neuroinflammation in ALS.
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