Type I Interferon α/β Receptor-Mediated Signaling Negatively Regulates Antiviral Cytokine Responses in Murine Bone-Marrow-Derived Mast Cells and Protects the Cells from Virus-Induced Cell Death.

Maedeh Darzianiazizi,Robert C Mould,Byram W Bridle,Shayan Sharif,Lily Chan,Raveendra R Kulkarni,Khalil Karimi,Yeganeh Mehrani

doi:10.3390/ijms21239041

Abstract

Mast cells (MCs) are critical for initiating inflammatory responses to pathogens including viruses. Type I interferons (IFNs) that exert their antiviral functions by interacting with the type I IFN receptor (IFNAR) play a central role in host cellular responses to viruses. Given that virus-induced excessive toxic inflammatory responses are associated with aberrant IFNAR signaling and considering MCs are an early source of inflammatory cytokines during viral infections, we sought to determine whether IFNAR signaling plays a role in antiviral cytokine responses of MCs. IFNAR-intact, IFNAR-blocked, and IFNAR-knockout (IFNAR−/−) bone-marrow-derived MCs (BMMCs) were treated in vitro with a recombinant vesicular stomatitis virus (rVSVΔm51) to assess cytokine production by these cells. All groups of MCs produced the cytokines interleukin-6 and tumor necrosis factor-α in response to rVSVΔm51. However, production of the cytokines was lowest in IFNAR-intact cells as compared with IFNAR−/− or IFNAR-blocked cells at 20 h post-stimulation. Surprisingly, rVSVΔm51 was capable of infecting BMMCs, but functional IFNAR signaling was able to protect these cells from virus-induced death. This study showed that BMMCs produced pro-inflammatory cytokines in response to rVSVΔm51 and that IFNAR signaling was required to down-modulate these responses and protect the cells from dying from viral infection.

Highlights

The biological role of mast cells (MCs) was initially attributed to allergic inflammation [1,2]
To explore the potential for MCs to be infected with rVSV, bone-marrow-derived MCs (BMMCs) were initially either treated with medium or WT rVSV encoding a transgene for full-length enhanced green fluorescent protein (GFP) at a multiplicity of infection (MOI) of 10
Flow cytometry data showed that a mean of 14.37% ± 1.02% of c-kit+FcεRIα+ BMMCs were positive for GFP expression at 10 h after exposure to the virus (Figure 1A)

Summary

Introduction

The biological role of mast cells (MCs) was initially attributed to allergic inflammation [1,2]. Induction of antiviral cytokines and chemokines by MCs appears to occur via retinoic acid-inducible gene I/mitochondrial antiviral signaling protein/melanoma differentiation-associated protein 5-mediated recognition of viral products leading to the induction of IFN-α and -β, and chemokines [24,25,26,27], independently of classical MC degranulation [24,28,29,30,31,32]. Human MCs have been shown to selectively induce certain types of inflammatory cytokines and chemokines in response to treatment with IFN-α2 and IFN-γ independently of degranulation [33,34]. Given the limited information on the role of type I IFN-mediated signaling on the modulation of antiviral responses of MCs, this was explored in this in vitro study using murine BMMCs

Methods

Results

Conclusion