Cofilin mediates LPS-induced microglial cell activation and associated neurotoxicity through activation of NF-κB and JAK-STAT pathway
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Microglial cells are activated in response to different types of injuries or stress in the CNS. Such activation is necessary to get rid of the injurious agents and restore tissue homeostasis. However, excessive activation of microglial cells is harmful and contributes to secondary injury. Pertinently, microglial cell activity was targeted in many preclinical and clinical studies but such strategy failed in clinical trials. The main reason behind the failed attempts is the complexity of the injury mechanisms which needs either a combination therapy or targeting a process that is involved in multiple pathways. Cofilin is a cytoskeleton-associated protein involved in actin dynamics. In our previous study, we demonstrated the role of cofilin in mediating neuronal apoptosis during OGD conditions. Previous studies on microglia have shown the involvement of cofilin in ROS formation and phagocytosis. However, additional studies are needed to delineate the role of cofilin in microglial cell activation. Therefore, in the current study, we investigated the role of cofilin in LPS-induced microglial cell activation using cofilin siRNA knockdown paradigms. The viability of differentiated PC12 cells was used as a measure of the neurotoxic potential of conditioned medium derived from cofilin siRNA-transfected and LPS-activated microglial cells. Cofilin knockdown significantly inhibited LPS-induced microglial cell activation through NF-κB and JAK-STAT pathways. The release of proinflammatory mediators (NO, TNF-α, iNOS, and COX2) as well as microglial proliferation and migration rates were significantly reduced by cofilin knockdown. Furthermore, differentiated PC12 cells were protected from the neurotoxicity induced by conditioned medium derived from cofilin-transfected and LPS-activated microglial cells. In conclusion, we demonstrated that cofilin is involved in the cascade of microglial cell activation and further validates our previous study on cofilin's role in mediating neuronal apoptosis. Together, our results suggest that cofilin could present a common target in neurons and microglial cells and might prove to be a promising therapy for different brain injury mechanisms including stroke.
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Ptgs2 (COX2) and Cybb (Nox-2) are considered proinflammatory mediators.
“Based on publicly available data in this model (Krasemann et al., 2017), we focused on the expression of the two highest induced genes upon repeated systemic LPS injections, Ptgs2 and Cybb (also known as Cox2 and Nox-2 respectively), where both genes are considered as proinflammatory mediators (Alhadidi and Shah, 2018; Benusa et al., 2017).”
From TET2 Regulates the Neuroinflammatory Response in Microglia (2019) · cites this paper as Alhadidi and Shah, 2018
The Introduction (page not provided) lists COX2 among the proinflammatory and cytotoxic substances associated with activated microglia, supporting that part of the claim. Our copy does not similarly identify Cybb/Nox-2 as a proinflammatory mediator; the references mention NADPH oxidase, but do not establish the attributed characterization. (LLM, conf=0.86)
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Meet the Editorial Board Member
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- Authors
- Alhadidi, Q., & Shah, Z. A.
- Affiliations
- Ministry of Health (IQ)
- University of Toledo (US)
- Corresponding author
- Shah, Zahoor A.
- ORCID
- Alhadidi, Qasim
- Venue
- Molecular Neurobiology
- Published
- 2017-02-13
- Volume
- 55
- Issue
- 2
- Pages
- 1676-1691
- ISSN
- 0893-7648 (ISSN-L)
- 1559-1182
- PMC
- PMC5554748
- OpenAlex
- W2588440731
- Cited by
- 83
- References
- 66
- Citations by year
- 2026: 5 · 2025: 6 · 2024: 12 · 2023: 10 · 2022: 11 · 2021: 7 · 2020: 15 · 2019: 6 · 2018: 7 · 2017: 4
- FWCI
- 4.50
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular Neurobiology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Center for Complementary and Integrative Health (R00AT004197)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Keywords
- cofilin, microglial activation, lipopolysaccharide, neuroinflammation, NF-κB signaling, JAK/STAT signaling, neurotoxicity, PC12 cells, pro-inflammatory mediators, TNF-α, inducible nitric oxide synthase, cyclooxygenase-2, nitric oxide, stroke, actin cytoskeleton
- MeSH terms
- Animals, Lipopolysaccharides, Neurons, Signal Transduction, NF-kappa B, PC12 Cells, Microglia, Cell Proliferation, STAT Transcription Factors, Cofilin 1, Rats, Janus Kinase 1
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