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

PLoS Biology, 2022 · DOI: https://doi.org/10.1371/journal.pbio.3001554 · Published: August 26, 2022

Simple Explanation

Multiple sclerosis (MS) is a demyelinating, neurodegenerative disease of the central nervous system (CNS). Through the modelling of MS using experimental autoimmune encephalomyelitis (EAE), we now understand that T cells play a central role in driving this disease. 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. 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.

Study Duration

28 days

Participants

WT C57BL/6JOlaHsD mice, cathelicidin KO (Camp KO) mice and LysMCre conditional KO mice

Evidence Level

Not specified

Key Findings

1
Cathelicidin is expressed by multiple cell types in lymphoid organs and the central nervous system during EAE, including neutrophils, endothelial cells and microglia/macrophages.
2
Cathelicidin is also expressed during human multiple sclerosis disease, specifically in active demyelinated lesions, with the majority of cathelicidin coming from neutrophils and a substantial minority from endothelial cells and microglia/macrophages.
3
Mice lacking cathelicidin are resistant to EAE disease, demonstrating that myeloid cell production of cathelicidin is sufficient for full disease penetrance.

Research Summary

This study demonstrates that the antimicrobial peptide cathelicidin drives severe autoimmune disease in the mouse model of MS. Exposure of CD4+ T cells in the draining lymph node to neutrophil-derived cathelicidin enhances their differentiation into Th17 cells. When these cells move into the CNS, they are further exposed to cathelicidin released by neutrophils, microglia, and endothelial cells, and this potentiates Th17 differentiation into IFN-γ producing “exTh17” cells. This work extends previous studies showing that neutrophils are important in autoimmune disease by providing a mechanism through which they can drive inflammation—the specific potentiation of IFN-γ-producing exTh17 cells in the CNS.

Practical Implications

Therapeutic target

Cathelicidin could be a therapeutic target for MS and other autoimmune diseases.

Neutrophil role

Highlights the role of neutrophils in driving inflammation in the CNS through cathelicidin.

T cell differentiation

Provides insight into the specific mechanisms by which cathelicidin influences T cell differentiation and pathogenicity.

Study Limitations

1
The study primarily uses a mouse model (EAE), and further research is needed to fully understand the role of cathelicidin in human MS.
2
The precise mechanisms by which cathelicidin is released and taken up by different cell types in the CNS remain unclear.
3
The relative contributions of microglia and neutrophils in the spinal cord to cathelicidin production and its effects on T cells require further investigation.

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