A Protective Role for Interleukin-1 Signaling during Mouse Adenovirus Type 1-Induced Encephalitis

Abstract

Interleukin-1␤ (IL-1␤), an inflammatory cytokine and IL-1 receptor ligand, has diverse activities in the brain. We examined whether IL-1 signaling contributes to the encephalitis observed in mouse adenovirus type 1 (MAV-1) infection, using mice lacking the IL-1 receptor (Il1r1 Ϫ/Ϫ mice). Il1r1 Ϫ/Ϫ mice demonstrated reduced survival, greater disruption of the blood-brain barrier (BBB), higher brain viral loads, and higher brain inflammatory cytokine and chemokine levels than control C57BL/6J mice. We also examined infections of mice defective in IL-1␤ production (Pycard Ϫ/Ϫ mice) and mice defective in trafficking of Toll-like receptors to the endosome (Unc93b1 Ϫ/Ϫ mice). Pycard Ϫ/Ϫ and Unc93b1 Ϫ/Ϫ mice showed lower survival (similar to Il1r1 Ϫ/Ϫ mice) than control mice but, unlike Il1r1 Ϫ/Ϫ mice, did not have increased brain viral loads or BBB disruption. Based on the brain cytokine levels, MAV-1-infected Unc93b1 Ϫ/Ϫ mice had a very different inflammatory profile from infected Il1r1 Ϫ/Ϫ and Pycard Ϫ/Ϫ mice. Histological examination demonstrated pathological findings consistent with encephalitis in control and knockout mice; however, intranuclear viral inclusions were seen only in Il1r1 Ϫ/Ϫ mice. A time course of infection of control and Il1r1 Ϫ/Ϫ mice evaluating the kinetics of viral replication and cytokine production revealed differences between the mouse strains primarily at 7 to 8 days after infection, when mice began succumbing to MAV-1 infection. In the absence of IL-1 signaling, we noted an increase in the transcription of type I interferon (IFN)-stimulated genes. Together, these results indicate that IL-1 signaling is important during MAV-1 infection and suggest that, in its absence, increased IFN-␤ signaling may result in increased neuroinflammation. IMPORTANCEThe investigation of encephalitis pathogenesis produced by different viruses is needed to characterize virus and host-specific factors that contribute to disease. MAV-1 produces viral encephalitis in its natural host, providing a good model for studying factors involved in encephalitis development. We investigated the role of IL-1 signaling during MAV-1-induced encephalitis. Unexpectedly, the lack of IL-1 signaling increased the mortality and inflammation in mice infected with MAV-1. Also, there was an increase in the transcription of type I IFN-stimulated genes that correlated with the observed increased mortality and inflammation. The findings highlight the complex nature of encephalitis and suggests that IL-1 has a protective effect for the development of MAV-1-induced encephalitis.

Short-term environmental enrichment, and not physical exercise, alleviate cognitive decline and anxiety from middle age onwards without affecting hippocampal gene expression

“…Similarly, IL-1R1 signaling mediates innate and acquired immune responses (Dinarello, 1988), associated with protection or aggravation of the disease states in the CNS, infections, and cancers (Durrant et al, 2014;Wolf et al, 1994). Knocking out these genes have shown to result in apoptotic cell death and affects brain functions and neurobiology adversely (Wang et al, 2011;Castro-Jorge et al, 2017;Becher et al, 2002). The upregulation of these three genes in all groups after PE at nine months suggests the neuroprotective role of PE, which has also been reported earlier (Campos et al, 2016).…”

Antibody and DNA sensing pathways converge to activate the inflammasome during primary human macrophage infection

“…The importance of inflammasomes and IL‐1β in particular in protecting against infection has been primarily studied in the context of bacterial infections. However, IL‐1β and inflammasome signalling pathways are required for the clearance of Mouse adenovirus‐1 (MAV1) infections in vivo (Castro‐Jorge et al , ). Similarly, TRIM21 is required for efficient antibody protection against MAV1 infection in vivo (Vaysburd et al , ).…”

Transcriptome Profiling Reveals Novel Candidate Genes Related to Hippocampal Dysfunction in SREBP-1c Knockout Mice

“…Some studies have demonstrated that the suppression or ablation of IL1R1 has a reparative role against neurotoxicity [45] and that it prevents the development of anxiety-like behavior in mice [46]. In contrast, another study found that the KO of IL-1R in mice exacerbated virus-induced cell death and neuroinflammation [47]. Because of the wide array of functions that IL1R1 is responsible for in different types of brain cells, further elucidation is required regarding the involvement and role of IL1R1 in the pathogenesis of brain disorders and their corresponding animal models.…”