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抗菌肽 cathelicidin 通过影响 Th17 分化来驱动实验性自身免疫性脑脊髓炎在小鼠中的发展。

The antimicrobial peptide cathelicidin drives development of experimental autoimmune encephalomyelitis in mice by affecting Th17 differentiation.

机构信息

Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom.

Centre for Reproductive Health, University of Edinburgh, Edinburgh, United Kingdom.

出版信息

PLoS Biol. 2022 Aug 26;20(8):e3001554. doi: 10.1371/journal.pbio.3001554. eCollection 2022 Aug.

Abstract

Multiple sclerosis (MS) is a highly prevalent demyelinating autoimmune condition; the mechanisms regulating its severity and progression are unclear. The IL-17-producing Th17 subset of T cells has been widely implicated in MS and in the mouse model, experimental autoimmune encephalomyelitis (EAE). However, the differentiation and regulation of Th17 cells during EAE remain incompletely understood. Although evidence is mounting that the antimicrobial peptide cathelicidin profoundly affects early T cell differentiation, no studies have looked at its role in longer-term T cell responses. Now, we report that cathelicidin drives severe EAE disease. It is released from neutrophils, microglia, and endothelial cells throughout disease; its interaction with T cells potentiates Th17 differentiation in lymph nodes and Th17 to exTh17 plasticity and IFN-γ production in the spinal cord. As a consequence, mice lacking cathelicidin are protected from severe EAE. In addition, we show that cathelicidin is produced by the same cell types in the active brain lesions in human MS disease. We propose that cathelicidin exposure results in highly activated, cytokine-producing T cells, which drive autoimmunity; this is a mechanism through which neutrophils amplify inflammation in the central nervous system.

摘要

多发性硬化症 (MS) 是一种高度流行的脱髓鞘自身免疫性疾病;调节其严重程度和进展的机制尚不清楚。产生白细胞介素-17 的 Th17 细胞亚群已广泛涉及 MS 和实验性自身免疫性脑脊髓炎 (EAE) 的发病机制。然而,EAE 期间 Th17 细胞的分化和调节仍不完全清楚。尽管越来越多的证据表明抗菌肽 cathelicidin 对早期 T 细胞分化有深远影响,但尚无研究探讨其在长期 T 细胞反应中的作用。现在,我们报告 cathelicidin 可导致严重的 EAE 疾病。它从中性粒细胞、小胶质细胞和血管内皮细胞在整个疾病过程中释放;它与 T 细胞的相互作用增强了淋巴结中的 Th17 分化,以及脊髓中的 Th17 向 exTh17 的可塑性和 IFN-γ 产生。因此,缺乏 cathelicidin 的小鼠可免受严重的 EAE 影响。此外,我们还表明,在人类 MS 疾病的活跃脑损伤中,同样的细胞类型也会产生 cathelicidin。我们提出,cathelicidin 的暴露导致高度激活、产生细胞因子的 T 细胞,从而驱动自身免疫;这是中性粒细胞在中枢神经系统中放大炎症的一种机制。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eb3e/9455863/fdaca7ff18b3/pbio.3001554.g001.jpg

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