Abstract
Post-stroke inflammation may contribute to secondary brain injury and systemic immunosuppression. Interleukin(IL)-37 is an immunosuppressive cytokine belonging to the IL-1 superfamily with no mouse homologue yet identified, the effects of which have not been studied in stroke. Here we report: (1) the effect of ischemic stroke on circulating IL-37 in humans; and (2) the effect of IL-37 on stroke outcome measures in mice transgenic for human IL-37 (IL-37tg). We found that in the first 3 days after ischemic stroke in 55 patients, the plasma abundance of IL-37 was ~2-fold higher than in 24 controls. In IL-37tg mice, cerebral ischemia-reperfusion resulted in marked increases in plasma IL-37 (~9-fold) and brain IL-37 mRNA (~7,000-fold) at 24 h compared with sham-operated IL-37tg mice. Further, compared with wild-type (WT) mice subjected to cerebral ischemia-reperfusion, IL-37tg mice exhibited less severe locomotor deficit, smaller cerebral infarcts and reduced bacterial lung infection. In the ischemic hemisphere, there were 60% fewer pro-inflammatory microglia-macrophages and up to 4-fold higher expression of anti-inflammatory markers in IL-37tg compared to WT mice. Our data show that IL-37 expression is increased following ischemic stroke in humans and IL-37tg mice, and may exert protective effects by modulating post-stroke inflammation in the brain and periphery.
Highlights
Stroke is a leading cause of death and disability, with more than 800,000 cases occurring annually in the USA alone[1]
In patients with acute ischemic stroke, the plasma abundance of IL-37 was approximately double that of control patients 3 days after the event (P = 0.038; Fig. 1a), but there was no correlation with two indicators of stroke severity – the National Institute of Health Stroke Scale (NIHSS, ρ = −0.14, P = 0.304) or Glasgow Coma Scale scores (ρ = 0.10, P = 0.488)
Ischemic stroke resulted in a marked increase in plasma IL-37 in both humans and IL-37tg mice
Summary
Stroke is a leading cause of death and disability, with more than 800,000 cases occurring annually in the USA alone[1]. Inflammation is initiated by the activation of resident microglia, followed by increases in cell adhesion molecules and chemokines, leading to the infiltration of immune cells through the blood-brain barrier[5,6]. Both innate and adaptive immune responses contribute to the post-ischemic inflammation. We have investigated: (1) the abundance of IL-37 in the blood of control and ischemic stroke patients, and in post-mortem brain sections; and (2) the effect of IL-37 on stroke outcome measures in mice transgenic for human IL-37 (IL-37tg). The mRNA encoding IL-37 contains an instability sequence such that, even under the control of the constitutively active CMV promoter in these IL-37tg mice, an inflammatory stimulus (e.g. as in the ischemic brain) is required for mRNA upregulation and protein production[19,26,28,32]
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