CXCL10/CXCR3 Signaling Induces Neural Senescence and Cognitive Impairments

Chemokine receptors belong to the G-protein-coupled receptors family, and multiple lines of emerging evidence suggest that several chemokines are elevated in aging associated with central nervous system disorders. Increased level of CXCL10 in the central nervous system is reported in several neurodegenerative diseases, including Multiple sclerosis, Alzheimer's disease, and Virus-associated dementia. We also observed significantly increased expression of CXCL10 and CXCR3 in the prefrontal cortex and hippocampus of aged C57BL/6J mice (12- and 18-month-old mice). This leads us to hypothesize that CXCL10, being a component of SASPs, may aggravate/perpetuate the brain aging process and, finally, neurodegenerative diseases. To test this hypothesis, we administered CXCL10 (intracerebroventricular: ICV, 0.5 pg/ hrs, 28 days) in 8-month-old C57BL/6J mice. We observed increased expression of senescent marker proteins p16INK4a, p21Cip1, and p53 and decreased expression of pRB in the prefrontal cortex, which was blocked by CXCR3-specific antagonist AMG487. Furthermore, chronic infusion of CXCL10 induced learning and memory deficits in Y-maze, social recognition and contextual freeze tests, and c-FOS expression in the prefrontal cortex. To further determine the specificity of CXCL10/CXCR3 signaling, we treated the primary cortical neuron (Days in vitro: DIV 7-8) with CXCL10 and found increased senescence in CXCR3 dependent fashion. Using GFP-RFP-LC3β transgenic mice, we also showed CXCL10/CXCR3 signaling attenuates autophagic flux in primary cortical neurons. Lastly, using a c-FOS-iRFP reporter, we observed that increased CXCL10/CXCR3 signaling impairs glutamatergic signaling in primary cortical neurons. These results support the hypothesis that increased CXCL10/CXCR3 facilitates brain aging and could be targeted for the management of aging-associated CNS disorders.