Social isolation alters neuroinflammatory response to stroke

Abstract

Social isolation has dramatic long-term physiological and psychological consequences; however, the mechanisms by which social isolation influences disease outcome are largely unknown. The purpose of the present study was to investigate the effects of social isolation on neuronal damage, neuroinflammation, and functional outcome after focal cerebral ischemia. Male mice were socially isolated (housed individually) or pair housed with an ovariectomized female before induction of stroke, via transient intraluminal middle cerebral artery occlusion (MCAO), or SHAM surgery. In these experiments, peri-ischemic social isolation decreases poststroke survival rate and exacerbates infarct size and edema development. The social influence on ischemic damage is accompanied by an altered neuroinflammatory response; specifically, central interleukin-6 (IL-6) signaling is down-regulated, whereas peripheral IL-6 is up-regulated, in isolated relative to socially housed mice. In addition, intracerebroventricular injection of an IL-6 neutralizing antibody (10 ng) eliminates social housing differences in measures of ischemic outcome. Taken together, these data suggest that central IL-6 is an important mediator of social influences on stroke outcome.

Fig. 1.

Effect of housing condition on ischemic damage after MCAO. (A) Percent infarct relative to the contralateral hemisphere is significantly increased in socially isolated mice after 24 h and 72 h of reperfusion. (B) Index of edema is also significantly increased in socially isolated mice at 48 h of reperfusion. ∗, significantly different from socially housed mice, P < 0.05.

Fig. 2.

Poststroke gene expression of MAC-1 and GFAP in striatum measured via RT-PCR. Within the ipsilateral hemisphere, both MAC-1 and GFAP are significantly up-regulated in socially isolated relative to socially housed mice. Data are presented as gene expression relative to control gene (18S) expression. ∗, significantly different from socially housed mice, P < 0.05.

Fig. 3.

Relative gene expression and protein concentration of poststroke IL-6. In the CNS, striatal IL-6 mRNA gene expression measured via RT-PCR (A) and cortical protein concentration measured via ELISA (B) are significantly down-regulated in the ischemic hemisphere of socially isolated relative to socially housed mice. (C) Serum IL-6 measured via ELISA is up-regulated in socially isolated mice. Gene and protein expression data in the CNS are presented as a ratio of ischemic to nonischemic hemisphere concentrations. ∗, significantly different from socially housed mice, P < 0.05.

Fig. 4.

Infarct volume and serum IL-6 protein concentrations after ICV treatment with IL-6 neutralizing antibody. (A) Treatment with 10 ng of IL-6 neutralizing antibody significantly increases infarct volume of socially housed mice and eliminates the effect of social interaction achieved with vehicle treatment. (B) Serum IL-6 is up-regulated in vehicle-treated socially isolated mice relative to socially housed mice, but treatment with the IL-6 neutralizing antibody eliminates the difference in serum IL-6 concentrations. ∗, significantly different from socially housed mice; #, significantly different from aCSF-treated mice, P < 0.05.