Exogenous inter-α inhibitor proteins prevent cell death and improve ischemic stroke outcomes in mice
Louise D. McCullough, … , Yow-Pin Lim, Venugopal Reddy Venna
Louise D. McCullough, … , Yow-Pin Lim, Venugopal Reddy Venna
Published September 1, 2021
Citation Information: J Clin Invest. 2021;131(17):e144898. https://doi.org/10.1172/JCI144898.
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Research Article Inflammation Neuroscience

Exogenous inter-α inhibitor proteins prevent cell death and improve ischemic stroke outcomes in mice

Abstract

Inter-α inhibitor proteins (IAIPs) are a family of endogenous plasma and extracellular matrix molecules. IAIPs suppress proinflammatory cytokines, limit excess complement activation, and bind extracellular histones to form IAIP-histone complexes, leading to neutralization of histone-associated cytotoxicity in models of sepsis. Many of these detrimental processes also play critical roles in the pathophysiology of ischemic stroke. In this study, we first assessed the clinical relevance of IAIPs in stroke and then tested the therapeutic efficacy of exogenous IAIPs in several experimental stroke models. IAIP levels were reduced in both ischemic stroke patients and in mice subjected to experimental ischemic stroke when compared with controls. Post-stroke administration of IAIP significantly improved stroke outcomes across multiple stroke models, even when given 6 hours after stroke onset. Importantly, the beneficial effects of delayed IAIP treatment were observed in both young and aged mice. Using targeted gene expression analysis, we identified a receptor for complement activation, C5aR1, that was highly suppressed in both the blood and brain of IAIP-treated animals. Subsequent experiments using C5aR1-knockout mice demonstrated that the beneficial effects of IAIPs are mediated in part by C5aR1. These results indicate that IAIP is a potential therapeutic candidate for the treatment of ischemic stroke.

Authors

Louise D. McCullough, Meaghan Roy-O’Reilly, Yun-Ju Lai, Anthony Patrizz, Yan Xu, Juneyoung Lee, Aleah Holmes, Daniel C. Kraushaar, Anjali Chauhan, Lauren H. Sansing, Barbara S. Stonestreet, Liang Zhu, Julia Kofler, Yow-Pin Lim, Venugopal Reddy Venna

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Figure 2

Immediate administration of exogenous IAIP reduces infarct size after MCAO in a dose-dependent manner.

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Immediate administration of exogenous IAIP reduces infarct size after MC...
(A) The experimental timeline. (B) Total hemispheric infarct volume measurements were determined using TTC-stained brain sections. Significant protection is seen with IAIP treatment at doses of 30 and 45 mg/kg (PBS vs. IAIP 30 mg/kg, ***P = 0.0001; PBS vs. IAIP 45 mg/kg, ****P < 0.0001; 1-way ANOVA adjusted for multiple testing). (C) Representative TTC-stained images of vehicle-treated (control) and IAIP-treated (30 mg/kg) brains from young stroke mice (90 minutes MCAO, 24 hours reperfusion) treated immediately after stroke. (D) Quantification of infarct volumes shows a significant reduction in cortex, striatum, and total hemisphere at 24 hours after stroke (vehicle vs. IAIP 30 mg/kg, mean ± SEM; ***P = 0.0004, ****P < 0.0001, 2-sample t test adjusted for multiple testing). (E) IAIP treatment significantly reduced NDS compared with vehicle treatment. Data are presented as median and interquartile range (**P = 0.0057, Wilcoxon’s rank sum test). (F) Percentage of water content in ipsilateral (Ipsi) and contralateral (Contra) hemispheres of young vehicle- and IAIP-treated mice (***P = 0.0005, t test adjusted for multiple testing).