| First Author | Markarian M | Year | 2021 |
| Journal | Cancer Res | Volume | 81 |
| Issue | 7 | Pages | 1732-1744 |
| PubMed ID | 33323383 | Mgi Jnum | J:305590 |
| Mgi Id | MGI:6706817 | Doi | 10.1158/0008-5472.CAN-20-2565 |
| Citation | Markarian M, et al. (2020) Glia-selective deletion of complement C1q prevents radiation-induced cognitive deficits and neuroinflammation. Cancer Res |
| abstractText | Adverse neurocognitive sequelae following clinical radiation therapy (RT) for CNS malignancies are often long-lasting and lack any clinical recourse. Despite recent progress, the cellular mechanisms mediating RT-induced cognitive deficits (RICD) are poorly understood. The complement system is an immediate sensor of a disturbed inflammatory environment and a potent mediator of gliosis with a range of non-immune functions in the CNS, including synaptic pruning which is detrimental if dysregulated. We hypothesize that complement-mediated changes in glial cell function significantly contribute to RICD. Underlying alterations in CNS complement cascade proteins (C1q, C3), TLR4 and, co-labeling with glia (IBA1, GFAP) were examined using gene expression, immunofluorescence and in silico modeling approaches in the adult mouse brain following 9 Gy cranial RT. 3D volumetric quantification showed elevated molecular signatures of gliosis at short- and long-term post-RT times. Following RT, significant elevations in complement C1q, C3 and TLR4 were accompanied by increased co-labeling of astrocytes and microglia. To address the mechanism of RT-induced complement cascade activation, neuroinflammation, and cognitive dysfunction, conditional, microglia-selective C1q (Flox) knockdown mice were used to determine whether a glia-specific, upstream complement cascade contributed to RICD. C1q-Flox mice exposed to cranial RT showed no cognitive deficits compared to irradiated WT mice. Irradiated C1q-Flox mice were protected from RT-induced microglial activation and synaptic loss and elevation of anaphylatoxin C5a receptor, astrocytic C3, and microglial TLR4 expression in the brain. Our findings demonstrate for the first time a microglia-specific mechanism of RICD involving an upstream complement cascade component, C1q. |
