Social disruption induced priming of CNS inflammatory response to Theiler's virus is dependent upon stress induced IL-6 release

Abstract

Chronic social disruption stress (SDR) exacerbates acute and chronic phase Theiler’s murine encephalomyelitis virus (TMEV) infection, a mouse model of multiple sclerosis. However, the precise mechanism by which this occurs remains unknown. The present study suggests SDR exacerbates TMEV disease course by priming virus-induced neuroinflammation. It was demonstrated that IL-1β mRNA expression increases following acute SDR; however, IL-6 mRNA expression, but not IL-1β, is upregulated in response to chronic SDR. Furthermore, this study demonstrated SDR prior to infection increases infection related central IL-6 and IL-1β mRNA expression, and administration of IL-6 neutralizing antibody during SDR reverses this increase in neuroinflammation.

Chronic social stress impairs virus specific adaptive immunity during acute Theiler's virus infection

“…Both Th2 and Th17 responses have been linked with autoimmune disease susceptibility in animal models (Bettelli et al, 2007; Carding et al, 1993; Chen et al, 2006; Komiyama et al, 2006; Sutton et al, 2006; Ramsey et al, 1993; Rangachari et al, 2006) as well as impaired viral clearance (Hou et al, 2009). The current findings are consistent with the hypothesis that sensitization of the early proinflammatory cytokine response within the CNS translates into an impaired adaptive immune response (Vichaya et al, 2011). …”

“…Social stress has previously been shown to stimulate and/or sensitize the innate proinflammatory cytokine response (Meagher et al, 2007; Quan et al, 2001; Vichaya et al, 2011). In the TMEV model specifically, we have found that SDR alone increases circulating and CNS levels of the pro-inflammatory cytokine IL-6 and blocking IL-6 activity during SDR exposure attenuates the exacerbation of the acute TMEV disease (Meagher et al, 2007; Vichaya et al, 2010 ).…”

“…We have shown that social disruption (SDR) stress prior to TMEV infection exacerbates both the acute and chronic phases of disease (Johnson et al, 2004, 2006, Meagher et al, 2007; Vichaya et al, 2011), however, the mechanism by which this occurs remains to be fully elucidated. SDR exposure results in enhanced CNS inflammation, increased behavioral signs of encephalomyelitis, and impaired clearance of the virus from CNS during early infection (Meagher et al, 2007).…”

“…SDR exposure results in enhanced CNS inflammation, increased behavioral signs of encephalomyelitis, and impaired clearance of the virus from CNS during early infection (Meagher et al, 2007). More recently, we have demonstrated that SDR increases both baseline and infection-induced proinflammatory cytokine mRNA levels in the CNS (Vichaya et al, 2011). Social defeat is potent modulator of both macrophage trafficking from the periphery into the CNS and the inflammatory potential of microglia and CNS macrophages, both of which might be expected to improve viral clearance by ramping up the immune response to a given challenge (Wohleb et al, 2012).…”

Stress and the anti-influenza immune response: Repeated social defeat augments clonal expansion of CD8+T cells during primary influenza A viral infection

“…LCMV is a systemic infection with a very different tissue tropism and infectious course than IAV, which makes it difficult to directly compare the effect of SDR on immune parameters in each viral system. In a mouse model of a neurotropic virus infection, Theiler’s murine encephalomyelitis virus, SDR prior to infection exacaberated disease by priming virus-induced neuroinflammation, however, the experience of the social stressor during infection had beneficial effects on clinical disease course and inflammation (Johnson et al, 2004; Vichaya et al, 2011). These differences underscore the importance of both the timing of the stressor and the cellular infectious profile of the viral agent used when comparing neuroendocrine regulation of replicating antigens.…”