The antimicrobial peptide cathelicidin is critical for the development of Th17 responses in severe inflammatory disease
The antimicrobial peptide cathelicidin is critical for the development of Th17 responses in severe inflammatory disease
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DOI：
10.1101/2022.01.27.477976
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发表时间：
2022-01
期刊：
影响因子：
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通讯作者：
K. Smith;Danielle Minns;B. McHugh;Rebecca K. Holloway;R. O’Connor;Anna C. Williams;L. Melrose;Rhoanne C. McPherson;V. Miron;D. Davidson;E. Findlay
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文献类型：
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作者：
K. Smith;Danielle Minns;B. McHugh;Rebecca K. Holloway;R. O’Connor;Anna C. Williams;L. Melrose;Rhoanne C. McPherson;V. Miron;D. Davidson;E. Findlay
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il -17的T细胞Th17亚群广泛参与MS和小鼠模型实验性自身免疫性脑脊髓炎（EAE）。然而，在EAE过程中Th17细胞的分化和调控尚不完全清楚。尽管越来越多的证据表明抗菌肽cathelicidin深刻影响早期T细胞分化，但没有研究关注其在长期T细胞反应中的作用。现在，我们报道了cathelicidin导致严重的EAE疾病。它在整个疾病过程中由中性粒细胞、小胶质细胞和内皮细胞释放；它与T细胞的相互作用增强了Th17在淋巴结中的分化，并增强了Th17在脊髓中的可塑性和IFN-γ的产生。因此，缺乏抗菌肽的小鼠可以避免严重的EAE。此外，我们发现在人类多发性硬化症的活动性脑病变中，cathelicidin是由相同类型的细胞产生的。我们认为，抗菌肽暴露导致高度活化的细胞因子产生T细胞，从而驱动自身免疫；这是中性粒细胞放大中枢神经系统炎症的一种机制。
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.