The neutrophil antimicrobial peptide cathelicidin promotes Th17 differentiation.

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

doi:10.1038/s41467-021-21533-5

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.

Highlights

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
In isolated CD4+ T cells exposed to cathelicidin for 24 h under Th17-driving conditions, STAT3 phosphorylation was significantly enhanced (Fig. 1L–N)
Analysis of CD4+ T cells exposed to cathelicidin in Th17-driving conditions revealed that this receptor—and IL-6R and IL-23R—were unaltered (Fig. 2B, C)

Summary

Introduction

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. Release of HDP, such as cathelicidin, is a critical part of the first line innate immune response to infection[43,44] and it is antibacterial, antiviral, antifungal and immunomodulatory[45,46,47], with potent ability to modulate the local innate and adaptive immune response Amongst other effects, it can act as a chemoattractant for immune cells[48,49], promote protective inflammatory responses and modulate cell death[50,51], induce wound healing, re-epithelialization and re-endothelialization[52,53], allow the take-up of self-RNA and production of type one interferons by plasmacytoid DC54,55 and inhibit class switching in B cells[56]

Methods

Results

Conclusion