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

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.

Murine Mast Cells That Are Deficient in IFNAR-Signaling Respond to Viral Infection by Producing a Large Amount of Inflammatory Cytokines, a Low Level of Reactive Oxygen Species, and a High Rate of Cell Death

“…Our previous study demonstrated that rVSVΔm51 was capable of infecting BMMCs, as was evidenced by the decreasing trend in cell viability in virus-treated cells over the course of infection [ 2 ]. While all virus-treated cells displayed a reduction in cell viability following infection with rVSVΔm51, IFNAR−/− BMMCs had the lowest number of viable cells compared to BMMCs IFNAR+/+.…”

“…They possess unique capabilities contributing to the body’s defense mechanism against viral infections. One of their functions includes degranulation, during which these cells release inflammatory cytokines such as IL-6 and TNF-α [ 2 ]. This process aids in initiating and coordinating immune responses against viral invaders.…”

“…IFNAR-knockout (IFNAR−/−) BMMCs produced dramatically higher concentrations of the inflammatory cytokines IL-6 and TNF-α than IFNAR-intact (IFNAR+/+) BMMCs. Additionally, cell death was increased upon viral infection in MCs with disrupted type I IFN signaling compared to MCs with BMMCs IFNAR+/+; this was again monitored with flow cytometry [ 2 ].…”

Cytokine Storm Syndrome in SARS-CoV-2 Infections: A Functional Role of Mast Cells

“…MCs are granulated leukocytes [ 12 ] that reside in mucosal interfaces in close contact with the environment to respond to environmental challenges [ 13 ] and infectious organisms [ 14 , 15 , 16 ]. Recent studies showed that MCs are key effector cells of the innate immune system, and during viral infections they release several inflammatory mediators and cytokines, including histamine and IL-6 [ 17 , 18 ]. Histamine can contribute to the progression of inflammatory responses in many cell types and local tissues by enhancing the secretion of pro-inflammatory cytokines, such as IL-1α, IL-1β, IL-6, and chemokine (C-C motif) ligand 3 (CCL3) [ 19 ].…”

Mast Cells: When the Best Defense Is an Attack?

“…Multiple virus-associated stimuli can induce the production of type I and III IFNs, chemokines, inflammatory cytokines, as well as factors involved in tissue remodeling such as VEGF. In this issue, Darzianiazizi et al [ 1 ] show that bone-marrow-derived MCs produced pro-inflammatory cytokines in response to recombinant vesicular stomatitis virus and that type I IFN receptor (IFNAR) signaling was required to downregulate these responses and protect the cells from dying from viral infection. This suggests that IFNAR signaling plays a central role in the antiviral cytokine responses of MCs.…”