The NLRP3 inflammasome pathway contributes to chronic inflammation in experimental autoimmune uveitis

Q1 Health Professions
Avik Shome, Ilva D. Rupenthal, Rachael L. Niederer, Odunayo O. Mugisho
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Abstract

Background

Noninfectious uveitis, a chronic ocular inflammatory disease, is characterized by the activation of immune cells in the eye, with most studies focusing on the role of the adaptive immune system in the disease. However, limited data exist on the potential contribution of the innate immune system, specifically the nucleotide-binding oligomerization domain and leucine-rich repeat receptor-3 (NLRP3) inflammasome pathway. This pathway has previously been identified as a driver of inflammation in several low-grade, progressive inflammatory eye diseases such as diabetic retinopathy. The aim of this study was to determine whether the NLRP3 inflammasome pathway plays a role in the pathogenesis and chronicity of experimental autoimmune uveitis (EAU).

Methods

EAU was induced in C57BL/6J mice via intraperitoneal pertussis toxin and subcutaneous interphotoreceptor retinoid-binding protein injections. After 12 weeks, eyes were enucleated, and whole eye sections were assessed for inflammasome, macrophage, and microglial markers in the retina, ciliary body, and cornea using immunohistochemistry.

Results

Our study confirmed higher NLRP3 inflammasome activation (increased expression of NLRP3 and cleaved caspase 1 labeling) in EAU mouse retinas compared to controls. This correlated with increased astrogliosis and microglial activation throughout the eye. Migratory innate and adaptive peripheral immune cells (macrophages and leukocytes) were also found within the retina and ciliary body of EAU mice. Connexin43 proteins, which form hexameric hemichannels that can release adenosine triphosphate (ATP), an upstream inflammasome priming signal, were also found upregulated in the retina and cornea of EAU mice.

Conclusion

Overall, our findings support the idea that in the EAU model there is active inflammation, even 12 weeks post induction, and that it can be correlated to inflammasome activation. This contributes to the pathogenesis and chronicity of noninfectious uveitis, and our results emphasize that targeting the inflammasome pathway could be efficacious for noninfectious uveitis treatment.

Abstract Image

NLRP3炎症小体通路导致了实验性自身免疫性葡萄膜炎的慢性炎症。
背景:非感染性葡萄膜炎是一种慢性眼部炎症性疾病,其特征是眼睛免疫细胞的激活,大多数研究集中在适应性免疫系统在该疾病中的作用。然而,关于先天免疫系统的潜在贡献,特别是核苷酸结合寡聚化结构域和富含亮氨酸重复受体-3 (NLRP3)炎症小体途径的数据有限。这一途径此前已被确定为几种低级别进行性炎性眼病(如糖尿病视网膜病变)的炎症驱动因素。本研究的目的是确定NLRP3炎症小体通路是否在实验性自身免疫性葡萄膜炎(EAU)的发病机制和慢性性中起作用。方法:通过腹腔注射百日咳毒素和皮下注射视黄酮结合蛋白诱导C57BL/6J小鼠EAU。12周后,取眼去核,用免疫组织化学方法评估全眼视网膜、睫状体和角膜中的炎性体、巨噬细胞和小胶质细胞标志物。结果:我们的研究证实,与对照组相比,EAU小鼠视网膜中NLRP3炎性体活化(NLRP3和裂解caspase 1标记的表达增加)更高。这与整个眼睛星形胶质细胞增生和小胶质细胞激活增加有关。在EAU小鼠的视网膜和睫状体内也发现迁移性先天和适应性外周免疫细胞(巨噬细胞和白细胞)。Connexin43蛋白形成六聚体半通道,可以释放三磷酸腺苷(ATP),这是一种上游炎症体启动信号,在EAU小鼠的视网膜和角膜中也被发现上调。结论:总体而言,我们的研究结果支持EAU模型中存在活动性炎症的观点,甚至在诱导后12周,并且它可能与炎性小体激活有关。这有助于非感染性葡萄膜炎的发病机制和慢性,我们的研究结果强调,靶向炎性体途径可能是有效的非感染性葡萄膜炎治疗。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
5.50
自引率
0.00%
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0
审稿时长
12 weeks
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