The neutrophil antimicrobial peptide cathelicidin promotes Th17 differentiation

Danielle Minns; Katie J. Smith; Virginia Alessandrini; Gareth Hardisty; Lauren Melrose; Lucy  Jackson-Jones; Andrew S  MacDonald; Donald J Davidson; Emily L Gwyer Findlay

doi:10.1038/s41467-021-21533-5

The neutrophil antimicrobial peptide cathelicidin promotes Th17 differentiation

Danielle Minns, Katie J. Smith, Virginia Alessandrini, Gareth Hardisty, Lauren Melrose, Lucy Jackson-Jones, Andrew S MacDonald, Donald J Davidson, Emily L Gwyer Findlay

Research output: Contribution to journal › Article › peer-review

Abstract / Description of output

The host defence peptide cathelicidin (LL-37 in humans, mCRAMP in mice) is released from neutrophils by de-granulation, NETosis and necrotic death; it has potent anti-pathogen activity as well as being a broad immunomodulator. Here we report that cathelicidin is a powerful Th17 potentiator which enhances aryl hydrocarbon receptor (AHR) and RORγt expression, in a TGF-β1-dependent manner. In the presence of TGF-β1, cathelicidin enhanced SMAD2/3 and STAT3 phosphorylation, and profoundly suppressed IL-2 and T-bet, directing T cells away from Th1 and into a Th17 phenotype. Strikingly, Th17 but not Th1 cells were protected from apoptosis by cathelicidin. We show that cathelicidin is released by neutrophils in mouse lymph nodes and that cathelicidin-deficient mice display suppressed Th17 responses during inflammation, but not at steady state. We propose that the neutrophil cathelicidin is required for maximal Th17 differentiation, and that this is one method by which early neutrophilia directs subsequent adaptive immune responses.

Original language	English
Journal	Nature Communications
DOIs	https://doi.org/10.1038/s41467-021-21533-5
Publication status	Published - 24 Feb 2021

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10.1038/s41467-021-21533-5

s41467-021-21533-5
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The neutrophil antimicrobial peptide cathelicidin drives Th17 responses during infection
Gwyer Findlay, E.
UK-based charities
15/07/19 → 14/01/21
Project: Research
Cathelicidin is critical for pathogenic T cell development in Multiple Sclerosis
Gwyer Findlay, E.
UK-based charities
1/12/17 → 31/08/22
Project: Research
Determination of T cell signalling pathway alterations induced by the neutrophil peptide LL-37
Gwyer Findlay, E.
UK-based charities
1/10/17 → 30/09/18
Project: Research

Host and Tumour Profiling Unit (HTPU) Microarray Services
Alison Munro (Manager) & Kenneth Macleod (Other)
Deanery of Molecular, Genetic and Population Health Sciences
Facility/equipment: Facility

Cite this

@article{d5a28613eb2b4773bbce24434344e6f1,

title = "The neutrophil antimicrobial peptide cathelicidin promotes Th17 differentiation",

abstract = "The host defence peptide cathelicidin (LL-37 in humans, mCRAMP in mice) is released from neutrophils by de-granulation, NETosis and necrotic death; it has potent anti-pathogen activity as well as being a broad immunomodulator. Here we report that cathelicidin is a powerful Th17 potentiator which enhances aryl hydrocarbon receptor (AHR) and RORγt expression, in a TGF-β1-dependent manner. In the presence of TGF-β1, cathelicidin enhanced SMAD2/3 and STAT3 phosphorylation, and profoundly suppressed IL-2 and T-bet, directing T cells away from Th1 and into a Th17 phenotype. Strikingly, Th17 but not Th1 cells were protected from apoptosis by cathelicidin. We show that cathelicidin is released by neutrophils in mouse lymph nodes and that cathelicidin-deficient mice display suppressed Th17 responses during inflammation, but not at steady state. We propose that the neutrophil cathelicidin is required for maximal Th17 differentiation, and that this is one method by which early neutrophilia directs subsequent adaptive immune responses.",

author = "Danielle Minns and Smith, {Katie J.} and Virginia Alessandrini and Gareth Hardisty and Lauren Melrose and Lucy Jackson-Jones and MacDonald, {Andrew S} and Davidson, {Donald J} and {Gwyer Findlay}, {Emily L}",

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doi = "10.1038/s41467-021-21533-5",

language = "English",

journal = "Nature Communications",

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T1 - The neutrophil antimicrobial peptide cathelicidin promotes Th17 differentiation

AU - Minns, Danielle

AU - Smith, Katie J.

AU - Alessandrini, Virginia

AU - Hardisty, Gareth

AU - Melrose, Lauren

AU - Jackson-Jones, Lucy

AU - MacDonald, Andrew S

AU - Davidson, Donald J

AU - Gwyer Findlay, Emily L

PY - 2021/2/24

Y1 - 2021/2/24

N2 - The host defence peptide cathelicidin (LL-37 in humans, mCRAMP in mice) is released from neutrophils by de-granulation, NETosis and necrotic death; it has potent anti-pathogen activity as well as being a broad immunomodulator. Here we report that cathelicidin is a powerful Th17 potentiator which enhances aryl hydrocarbon receptor (AHR) and RORγt expression, in a TGF-β1-dependent manner. In the presence of TGF-β1, cathelicidin enhanced SMAD2/3 and STAT3 phosphorylation, and profoundly suppressed IL-2 and T-bet, directing T cells away from Th1 and into a Th17 phenotype. Strikingly, Th17 but not Th1 cells were protected from apoptosis by cathelicidin. We show that cathelicidin is released by neutrophils in mouse lymph nodes and that cathelicidin-deficient mice display suppressed Th17 responses during inflammation, but not at steady state. We propose that the neutrophil cathelicidin is required for maximal Th17 differentiation, and that this is one method by which early neutrophilia directs subsequent adaptive immune responses.

AB - The host defence peptide cathelicidin (LL-37 in humans, mCRAMP in mice) is released from neutrophils by de-granulation, NETosis and necrotic death; it has potent anti-pathogen activity as well as being a broad immunomodulator. Here we report that cathelicidin is a powerful Th17 potentiator which enhances aryl hydrocarbon receptor (AHR) and RORγt expression, in a TGF-β1-dependent manner. In the presence of TGF-β1, cathelicidin enhanced SMAD2/3 and STAT3 phosphorylation, and profoundly suppressed IL-2 and T-bet, directing T cells away from Th1 and into a Th17 phenotype. Strikingly, Th17 but not Th1 cells were protected from apoptosis by cathelicidin. We show that cathelicidin is released by neutrophils in mouse lymph nodes and that cathelicidin-deficient mice display suppressed Th17 responses during inflammation, but not at steady state. We propose that the neutrophil cathelicidin is required for maximal Th17 differentiation, and that this is one method by which early neutrophilia directs subsequent adaptive immune responses.

U2 - 10.1038/s41467-021-21533-5

DO - 10.1038/s41467-021-21533-5

M3 - Article

SN - 2041-1723

JO - Nature Communications

JF - Nature Communications

ER -

The neutrophil antimicrobial peptide cathelicidin promotes Th17 differentiation

Abstract / Description of output

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Projects

The neutrophil antimicrobial peptide cathelicidin drives Th17 responses during infection

Cathelicidin is critical for pathogenic T cell development in Multiple Sclerosis

Determination of T cell signalling pathway alterations induced by the neutrophil peptide LL-37

Equipment

Host and Tumour Profiling Unit (HTPU) Microarray Services

Cite this