Neurturin regulates the lung-resident macrophage inflammatory response to viral infection.

Emma Connolly,Miriam Franklin,David J Morgan,Angela Simpson,Christopher P Jagger,Rajesh Shah,Joshua Casulli,Tracy Hussell,Oliver J Brand,Karishma Mohamed,Aleksander M Grabiec

doi:10.26508/lsa.202000780

Abstract

Lung-resident macrophages are crucial to the maintenance of health and in the defence against lower respiratory tract infections. Macrophages adapt to local environmental cues that drive their appropriate function; however, this is often dysregulated in many inflammatory lung pathologies. In mucosal tissues, neuro-immune interactions enable quick and efficient inflammatory responses to pathogenic threats. Although a number of factors that influence the antimicrobial response of lung macrophages are known, the role of neuronal factors is less well understood. Here, we show an intricate circuit involving the neurotrophic factor, neurturin (NRTN) on human lung macrophages that dampens pro-inflammatory cytokine release and modulates the type of matrix metalloproteinases produced in response to viral stimuli. This circuit involves type 1 interferon-induced up-regulation of RET that when combined with the glial cell line-derived neurotrophic factor (GDNF) receptor α2 (GFRα2) allows binding to epithelial-derived NRTN. Our research highlights a non-neuronal immunomodulatory role for NRTN and a novel process leading to a specific antimicrobial immune response by human lung-resident macrophages.

Highlights

Lower respiratory tract infections and chronic respiratory diseases are within the top four causes of mortality globally (Barnes, 2019)
GFRα2 and RET expression was further confirmed at the protein level, with GFRα2 expression observed in human lung macrophages and human monocytederived macrophages (MDMs) (Fig 1C and D), whereas the coreceptor RET was only detected in phorbol 12-myristate 13-acetate (PMA)-treated THP-1 macrophages (Fig 1D)
That Gfrα2 was expressed on monocytes and macrophages irrespective of their stage of differentiation, tissue location, or subtype, which suggests a fundamental role in macrophage biology

Summary

Introduction

Lower respiratory tract infections and chronic respiratory diseases are within the top four causes of mortality globally (Barnes, 2019). Understanding the inflammatory cascades involved in the pathogenesis of these diseases is critical in developing new therapeutics and alleviating the clinical burden Because of their location in the airways, lung-resident alveolar macrophages are in direct contact with the external environment and are at the first line of defence against infectious agents. Type I IFNs, in turn, trigger the JAK—signal transducers and activators of transcription (STAT) pathway, which leads to the activation of a large number of interferon stimulated genes (Ivashkiv & Donlin, 2014) These genes encode proteins that induce cell-intrinsic anti-viral defences, and cytokines and chemokines that are critical in the immune response to clear the threat (Rauch et al, 2013; Rusinova et al, 2013). The specific interferon-stimulated genes induced in macrophages by a given pathogen or TLR receptor and how this directs the ensuing inflammatory cascade, especially in humans, is largely unknown

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Conclusion