Peripheral viral challenge triggers hippocampal production of inflammatory proteins

Abstract

Peripheral viral infections increase seizure propensity and intensity in susceptible individuals. We have modeled this comorbidity by demonstrating that intraperitoneal (ip) injection of the conventional viral mimetic, polyinosinic-polycytidylic acid (PIC), renders the brain hypersusceptible to seizures induced by kainic acid (KA). At the molecular level, the hippocampus, which is the ictal site of KA-induced seizures, exhibits upregulated expression of messages encoding several inflammatory genes. Here, we profiled temporal expression of these genes at the protein level. Briefly, eight-week old female C57BL/6 mice were ip injected with 12 mg/kg of PIC and inflammatory proteins were quantified in the hippocampus and blood by ELISA. We found a robust but transient increase in blood concentration of IL-6, CXCL10, CCL2, CXCL9, CCL7 and CCL12 six hours after PIC challenge. CXCL1, IL1β, TNFα and CXCL2 featured a moderate increase. However, only four chemokines were increased in the hippocampus. CXCL10 showed the highest increase 6-12 h after PIC challenge, and its level dwindled to the baseline by 48 h. CXCL1, CXCl9 and CXCL2 were also transiently elevated but their maximal values were by an order of magnitude lower than the values for CXCL10. These results indicate that CXCL10 is the primary inflammatory protein generated in the hippocampus in response to PIC challenge, and that this chemokine may drive the development of seizure hypersusceptibility. In addition, the hippocampus featured a protracted increase in the levels of anaphylatoxins C3a and C5a, indicating the activation of the complement cascades.

Neuronal CXCL10/CXCR3 Axis Mediates the Induction of Cerebral Hyperexcitability by Peripheral Viral Challenge

“…We have previously shown that PIC challenge robustly upregulates cerebral expression of the Cxcl10 gene at the message Michalovicz and Konat, 2014) and protein (Petrisko and Konat, 2017) levels. Here, we found neurons to be the predominant cell type responsible for CXCL10 generation in the brain.…”

“…Eight-week old female C57BL/6J mice obtained from Charles River Laboratories (Wilmington, MA) were housed with free access to food and water in a humidity-and temperaturecontrolled rooms under a 12:12 h light-dark cycle. Female mice were used to be consistent with previous studies (Kirschman et al, 2011;Michalovicz and Konat, 2014;Hunsberger et al, 2016Hunsberger et al, , 2017Petrisko and Konat, 2017). Mice in all experimental groups were matched by weight prior to treatments.…”

“…At the molecular level, PIC challenge induces a fulminant but transient increase of several inflammatory cytokines (IFNβ, IL-6, IL1β, and TNFα) and chemokines (CXCL10, CCL2, CXCL9, CCL7, and CCL12) in the blood (Michalovicz and Konat, 2014;Petrisko and Konat, 2017). This "cytokine storm" in turn, leads to a robust generation of CXCL10 in the hippocampus, whereas other major inflammatory mediators are either only slightly elevated (CXCL1, CXCL2, CXCL9, IL-6), or unchanged (IL-1β, TNFα) (Petrisko and Konat, 2017). The expression of the Cxcl10 mRNA is also massively upregulated in the hippocampus following PIC challenge (Michalovicz and Konat, 2014), indicating that CXCL10 is produced in situ in the brain.…”

“…The present study was undertaken to identify cellular origin of cerebral CXCL10 production instigated by PIC challenge (Petrisko and Konat, 2017). We also appraised the cellular origin of CXCR3.…”