Bridging immune-neurovascular crosstalk via the immunomodulatory microspheres for promoting neural repair

IF 18 1区医学 Q1 ENGINEERING, BIOMEDICAL Bioactive Materials Pub Date : 2024-11-08 DOI:10.1016/j.bioactmat.2024.10.031

Tongtong Xu , Lin Gan , Wei Chen , Dandan Zheng , Hanlai Li , Shiyu Deng , Dongliang Qian , Tingting Gu , Qianyuan Lian , Gracie Shen , Qingzhu An , Wanlu Li , Zhijun Zhang , Guo-Yuan Yang , Huitong Ruan , Wenguo Cui , Yaohui Tang

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Abstract

The crosstalk between immune cells and the neurovascular unit plays a pivotal role in neural regeneration following central nervous system (CNS) injury. Maintaining brain immune homeostasis is crucial for restoring neurovascular function. In this study, an interactive bridge was developed via an immunomodulatory hydrogel microsphere to link the interaction network between microglia and the neurovascular unit, thereby precisely regulating immune-neurovascular crosstalk and achieving neural function recovery. This immunomodulatory crosstalk microsphere (MP/RIL4) was composed of microglia-targeted RAP12 peptide-modified interleukin-4 (IL-4) nanoparticles and boronic ester-functionalized hydrogel using biotin-avidin reaction and air-microfluidic techniques. We confirmed that the immunomodulatory microspheres reduced the expression of pro-inflammatory factors including IL-1β, iNOS, and CD86, while upregulating levels of anti-inflammatory factors such as IL-10, Arg-1, and CD206 in microglia. In addition, injection of the MP/RIL4 significantly mitigated brain atrophy volume in a mouse model of ischemic stroke, promoted neurobehavioral recovery, and enhanced the crosstalk between immune cells and the neurovascular unit, thus increasing angiogenesis and neurogenesis of stroke mice. In summary, the immunomodulatory microspheres, capable of orchestrating the interaction between immune cells and neurovascular unit, hold considerable therapeutic potential for ischemic stroke and other CNS diseases.

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通过免疫调节微球架起免疫-神经血管串扰的桥梁，促进神经修复

免疫细胞和神经血管单元之间的相互影响在中枢神经系统（CNS）损伤后的神经再生中起着关键作用。维持脑部免疫平衡对恢复神经血管功能至关重要。本研究通过免疫调节水凝胶微球开发了一种互动桥梁，将小胶质细胞和神经血管单元之间的互动网络连接起来，从而精确调节免疫-神经血管串扰，实现神经功能恢复。这种免疫调节串联微球（MP/RIL4）由小胶质细胞靶向 RAP12 肽修饰的白细胞介素-4（IL-4）纳米颗粒和硼酸酯功能化水凝胶组成，采用了生物素-avidin 反应和空气微流体技术。我们证实，免疫调节微球降低了小胶质细胞中IL-1β、iNOS和CD86等促炎因子的表达，同时上调了IL-10、Arg-1和CD206等抗炎因子的水平。此外，注射 MP/RIL4 还能显著减轻缺血性中风小鼠模型的脑萎缩体积，促进神经行为的恢复，并增强免疫细胞与神经血管单元之间的串联，从而增加中风小鼠的血管生成和神经再生。总之，免疫调节微球能够协调免疫细胞和神经血管之间的相互作用，对缺血性中风和其他中枢神经系统疾病具有相当大的治疗潜力。

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来源期刊

Bioactive Materials Biochemistry, Genetics and Molecular Biology-Biotechnology

CiteScore

28.00

自引率

6.30%

发文量

436

审稿时长

20 days

期刊介绍： Bioactive Materials is a peer-reviewed research publication that focuses on advancements in bioactive materials. The journal accepts research papers, reviews, and rapid communications in the field of next-generation biomaterials that interact with cells, tissues, and organs in various living organisms. The primary goal of Bioactive Materials is to promote the science and engineering of biomaterials that exhibit adaptiveness to the biological environment. These materials are specifically designed to stimulate or direct appropriate cell and tissue responses or regulate interactions with microorganisms. The journal covers a wide range of bioactive materials, including those that are engineered or designed in terms of their physical form (e.g. particulate, fiber), topology (e.g. porosity, surface roughness), or dimensions (ranging from macro to nano-scales). Contributions are sought from the following categories of bioactive materials: Bioactive metals and alloys Bioactive inorganics: ceramics, glasses, and carbon-based materials Bioactive polymers and gels Bioactive materials derived from natural sources Bioactive composites These materials find applications in human and veterinary medicine, such as implants, tissue engineering scaffolds, cell/drug/gene carriers, as well as imaging and sensing devices.