Rhinovirus-induced IFN\u03b2 expression is NF\u03baB-dependent and regulated by the macrophage microenvironment

Mandy Menzel,Hamid Akbarshahi,Lena Uller,Joakim Kosinski

doi:10.1038/s41598-019-50034-1

Mandy Menzel, Hamid Akbarshahi + Show 2 more

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https://doi.org/10.1038/s41598-019-50034-1

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Journal: Scientific Reports	Publication Date: Sep 16, 2019
Citations: 6	License type: open-access

Affiliation: Lund University

Abstract

Macrophages play an important role in asthma pathogenesis both in the inflammatory and resolution phase of the disease. Macrophages can acquire different polarisation states dependent on their microenvironment. It is yet unclear through which mechanism the microenvironment affects the anti-viral response in macrophages. We hypothesized that the macrophage microenvironment regulates rhinovirus-induced IFNβ expression. Murine bone marrow-derived monocytes and human differentiated THP-1 cells were stimulated with M-CSF or GM-CSF and IFNγ or IL-4/IL-13, respectively, to mimic a Th1 or Th2 environment. Macrophages were infected with rhinovirus and gene and protein levels of IFNβ and pattern recognition receptor expression were measured. In subsequent experiments an IκB kinase inhibitor was used to study the involvement of NFκB. Both murine and human M1-like macrophages exhibited higher levels of IFNβ and pattern recognition receptors after rhinovirus infection than M2-like macrophages. Blockage of NFκB resulted in a lower expression of rhinovirus-induced IFNβ in human M1-like macrophages while inducing a higher expression in M2-like macrophages, suggesting that the interferon response towards viral infection was mediated by NFκB. These findings could contribute to a better understanding of mechanisms causing reduced anti-viral responses at viral-induced exacerbations in asthma.

Highlights

Asthma is a chronic disease of the airways that presents as wheezing, shortness of breath and chest tightness
Induction of interferon β (IFNβ) was lower in macrophages stimulated with granulocyte macrophage-colony stimulatory factor (GM-CSF) than in macrophage-colony stimulatory factor (M-CSF) stimulated macrophages (p < 0.05; Fig. 1A)
Associated with this was a trend towards higher viral load in GM-CSF stimulated macrophages compared to macrophages stimulated with M-CSF after rhinovirus infection (Fig. 1B)

Summary

Introduction

Asthma is a chronic disease of the airways that presents as wheezing, shortness of breath and chest tightness. Characteristic of asthma is a reversible airway obstruction caused by bronchial smooth muscle constriction and inflammation in the lungs[1,2]. Environmental factors, such as allergens, play a fundamental role in the development of allergic asthma. Alveolar macrophages are involved in inflammatory responses, while interstitial macrophages are important for lung homeostasis[4]. M1 phenotype or the classical activation pathway is initiated upon Toll-like receptor (TLR) stimulation by microbial products and/or in presence of IFNγ, activating a Th1 type immune response. Dependent on the microenvironment macrophages can switch between these polarization phenotypes Besides these cytokine regulators, transcription factors can control macrophage polarisation. IKKβ deficient macrophages produce lower levels of IFNβ upon group B streptococcus infection[9]

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