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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 Article has an altmetric score of 76

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

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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 8

IAIP mediates its beneficial effects by suppressing C5aR1 expression in both blood and brain.

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IAIP mediates its beneficial effects by suppressing C5aR1 expression in ...
(A–C) NanoString analysis. (A) Analysis of stroke and sham brains revealed that complement activation is highly upregulated after stroke (n = 3 per group). (B) Vehicle- versus IAIP-treated groups revealed that the most predominant DEGs are mapped to complement suppression in the brains of aged stroke animals, analyzed at 72 hours after stroke (n = 3 per group). (C) IAIP also reduced stroke-induced complement pathway in blood of aged stroke mice (n = 3 per group). Complement changes are presented as heatmap. (D) STRING analysis of the top 60 DEGs from brain is plotted. C5aR1 showed a strong association with several of these mRNAs. (E) Independent analysis and validation of complement changes revealed that C5aR1 is significantly reduced in both brain (*P = 0.0281) and blood (*P = 0.0249) of IAIP- versus vehicle-treated groups (2-sample t test). (F) IAIP treatment significantly reduced C5aR1 expression on infiltrating neutrophils in aged male brains (**P = 0.0072, t test). (G and H) C5aR1-knockout mice had no significant benefit from IAIP treatment in terms of cortex (P = 0.4433), striatum (P = 0.3325), and total hemisphere (P = 0.6962) infarcts (2-sample t tests adjusted for multiple testing) (G) and NDS (accessed by Wilcoxon’s rank sum test) (H), suggesting that IAIP’s beneficial effects are mediated by C5aR1 signaling. Data are presented as mean ± SEM.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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