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

Katie Smith, Danielle Minns, Brian McHugh, Rebecca Holloway, Richard A O'Connor, Anna C Williams, Lauren Melrose, Rhoanne McPherson, Véronique E Miron, Donald J Davidson, Emily L Gwyer Findlay*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.
Original languageEnglish
JournalPLoS Biology
DOIs
Publication statusPublished - 26 Aug 2022

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