Microglial Modulation of Neuronal Autophagy: Uncovering Cytokine-Mediated Pathways

Autophagy, a conserved cellular degradation process, plays a critical role in clearing toxic protein aggregates. Its disruption has been linked to various pathological conditions, including neurodegenerative diseases. Mutations in autophagy-related genes are found in a subset of hereditary neurodegeneration cases, and autophagosome accumulation in post-mortem brains further supports this link. However, the exact pathological mechanisms remain unclear. Emerging evidence points to the role of microglia, the immune cells of the central nervous system, in the onset and progression of neurodegenerative diseases. Reactive microglia and elevated microglial cytokines have been observed in patients and animal models. While certain cytokines can modulate autophagy in different cell types, few have been studied in neurons. To explore how microglial secretions influence neuronal autophagy, this study aims to identify new microglia-secreted cytokines that regulate the autophagic process in neurons. Initial experiments revealed that conditioned media from BV2 microglia downregulated autophagy in SH-SY5Y neuroblastoma cell line. Two strategies to screen the microglial secretome for autophagy-modulating molecules were employed: direct analysis of secreted cytokines and functional screening via knockout of neuronal cytokine receptors. However, no negative regulators of autophagy were found. Instead, two receptor-ligand pairs, CXCR5-CXCL13 and CXCR3-CXCL10, were identified as inducers of autophagy. CXCL13, the ligand for CXCR5, enhanced autophagy in several neuronal models, including primary mouse neurons and iPSC-derived neurons. Similarly, CXCL10 promoted autophagy in SH-SY5Y cell line and iPSC-derived neurons. CXCL10-induced autophagy was mediated by the CXCR3B isoform, while the CXCR3A isoform was found to inhibit autophagy when activated by CXCL9, another CXCR3 ligand. Both CXCL13 and CXCL10 triggered autophagy through activation of the JNK pathway, as shown by increased cJUN phosphorylation, and this effect was reversed by JNK inhibition. These findings highlight the significance of CXCR5 and CXCR3 signalling in modulating autophagy and suggest potential therapeutic targets for neurodegenerative diseases.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2024

Author dc:creator

• Rob, Matea

Advisor dc:contributor.advisor

• Rubinsztein, David

• Autophagy
• Neurodegeneration
• Cytokines

Licence

• https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/db096921-e806-458a-bbcd-5c5f46a3a8ed/download
• http://purl.org/NET/rdflicense/allrightsreserved

DOI dc:identifier.doi

https://doi.org/10.17863/CAM.119918

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/386949