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CKLF induces microglial activation via triggering defective mitophagy and mitochondrial dysfunction.
Hongyun Wang1, Junrui Ye1, Ye Peng2
1State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica & Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Autophagy
|November 1, 2023
Summary
Chemokine-like factor 1 (CKLF1) impairs mitophagy in microglia, leading to activation and neuroinflammation. Targeting this defective mitophagy offers a potential therapeutic strategy for brain inflammation.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Microglial activation is a key component of neuroinflammation, often triggered by chemokines.
- The specific role of mitophagy, the selective degradation of mitochondria via autophagy, in microglial activation remains poorly understood.
- Chemokine-like factor 1 (CKLF1) is an inducible chemokine found in the brain.
Purpose of the Study:
- To investigate the role of microglial mitophagy in CKLF1-induced microglial activation and neuroinflammation.
- To elucidate the molecular mechanisms underlying CKLF1's effects on mitophagy in microglia.
Main Methods:
- Analysis of mitophagy markers (DNM1L, PINK1, PRKN, OPTN) and autophagosome formation markers (BECN1, MAP1LC3B-II) in microglia following CKLF1 treatment.
- Assessment of mitophagy flux using SQSTM1 accumulation and confirmation via transmission electron microscopy and confocal microscopy.
- Evaluation of lysosomal function, including fusion, generation, and acidification.
- Pharmacological and gene-silencing approaches to block mitophagy and assess CKLF1-mediated microglial activation (AIF1 expression, Tnf and Il6 mRNA levels).
Main Results:
- CKLF1 treatment increased mitophagy markers and autophagosome formation but led to SQSTM1 accumulation, indicating reduced mitophagy flux and mitophagosome buildup.
- Impaired lysosomal function (impaired fusion, reduced generation, and acidification) was observed, causing damaged mitochondria accumulation in microglia.
- Blocking or silencing mitophagy inhibited CKLF1-induced microglial activation and pro-inflammatory cytokine production.
Conclusions:
- CKLF1 induces defective mitophagy in microglia by impairing lysosomal function, leading to mitochondrial accumulation.
- This defective mitophagy is a key driver of CKLF1-mediated microglial activation and subsequent neuroinflammation.
- Targeting CKLF1-induced mitophagy defects presents a potential therapeutic avenue for neuroinflammatory diseases.
