Activation of IP10/CXCR3 signaling with highly coincidental with PrPSc deposit in the brains of scrapie infected mice

Abstract

AbstractActivation of chemokine IP10, also named as CXCL10, and its receptor CXCR3 in CNS is described in some neurodegenerative diseases. Our previous study has also demonstrated an increased brain IP10 levels in several scrapie infected rodent models. However, the detailed alteration of IP10/CXCR3 signaling in CNS during prion infection remains unsettled. Here, we found the increased IP10 signals in the brains of scrapie infected mice mainly localized in the neurons using various methodologies. The levels of CXCR3 were markedly increased in brains of the scrapie infected mice and in the prion infected cell line SMB-S15. The increased CXCR3 is mainly distributed in neurons and activated microglia. Obviously morphological colocalizations of PrPC/PrPScwith IP10 and CXCR3 in the brains of scrapie infected mice were observed in the assays of immunohistochemistry (IHC) and immunofluorescence. Additionally, IHC analysis with whole brain sections demonstrated that the increased IP10 and CXCR3 accumulations occurred in the brain regions with more PrPScdeposits. Co-immunoprecipitation and biomolecular interaction assays identified the evidence for the molecular interactions of PrP with IP10 and CXCR3. Compared to the normal partner cell line SMB-PS, a larger amount of IP10 accumulated inside prion infected SMB-S15 cells. Suppression of prion replication in SMB-S15 cells by added resveratrol reverted the pattern of accumulation and secretion of cellular IP10 to that observed in SMB-PS cells. Our data here demonstrate an activation of IP10/CXCR3 signaling in prion-infected brain tissues that coincide with deposited PrPSc. Modulation of brain IP10/CXCR3 signaling is potential therapeutic target for reducing the progression of prion diseases.