The Response of Tissue Mast Cells to TLR3 Ligand Poly(I:C) Treatment

Abstract

Mast cells (MCs) are found mainly at the anatomical sites exposed to the external environment; thus, they are localized close to blood vessels, lymphatic vessels, and a multitude of immune cells. Moreover, those cells can recognize invading pathogens through a range of surface molecules known as pathogen recognition receptors (PRRs), mainly Toll-like receptors (TLRs). MCs are extensively engaged in the control and clearance of bacterial infections, but much less is known about their contribution to antiviral host response as well as pathomechanisms of virus-induced diseases. In the study, we employed in vivo differentiated mature tissue mast cells freshly isolated from rat peritoneal cavity. Here, we demonstrated that rat peritoneal mast cells (rPMCs) express viral dsRNA-specific TLR3 molecule (intracellularly and on the cell surface) as well as other proteins associated with cellular antiviral response: IRF3, type I and II IFN receptors, and MHC I. We found that exposure of rPMCs to viral dsRNA mimic, i.e., poly(I:C), induced transient upregulation of surface TLR3 (while temporarily decreased TLR3 intracellular expression), type II IFN receptor, and MHC I. TLR3 ligand-stimulated rPMCs did not degranulate but generated and/or released type I IFNs (IFN-α and IFNβ) as well as proinflammatory lipid mediators (cysLTs), cytokines (TNF, IL-1β), and chemokines (CCL3, CXCL8). We documented that rPMC priming with poly(I:C) did not affect FcεRI-dependent degranulation. However, their costimulation with TLR3 agonist and anti-IgE led to a significant increase in cysLT and TNF secretion. Our findings confirm that MCs may serve as active participants in the antiviral immune response. Presented data on modulated FcεRI-mediated MC secretion of mediators upon poly(I:C) treatment suggests that dsRNA-type virus infection could influence the severity of allergic reactions.

Toll-like receptor 3 (TLR3) regulation mechanisms and roles in antiviral innate immune responses

“…MCs have been reported to act as sentinel cells of innate immunity, extensively engaged in infection control and clearance (Piliponsky and Romani, 2018;Marshall et al, 2019). MCs express TLR3 molecules and other proteins associated with the cellular antiviral response, like IRF3, types I and II IFN receptors, and major histocompatibility complex (MHC) I (Witczak et al, 2020).…”

Mast cells: Therapeutic targets for COVID‐19 and beyond

“…34 , 44 , 47 Importantly, Mazzoni et al showed that COVID‐19 patients who required intensive care had high IL‐6 levels in their serum which were inversely correlated to the number of circulating NK cells that are critical for anti‐viral response. 83 In addition, Yang et al demonstrated that high plasma levels of CCL3 and CXCL10, 89 which can be produced by Poly (I:C)‐activated MCs, 90 are highly associated with disease severity during COVID‐19 infection, suggesting that uncontrolled inflammation results in “cytokine storm” and thereby disease deterioration and fatal outcome of COVID‐19. Additionally, histamine, prostaglandin (eg.…”

The pLysRS-Ap4A Pathway in Mast Cells Regulates the Switch from Host Defense to a Pathological State

“…Their Toll-like receptors (TLRs) are surface pathogen recognition receptors (PRRs) that can directly activate mast cells and help in controlling bacterial infections [ 3 ]. In addition to microbial challenges, an anti-viral response mechanism in rat peritoneal mast cells (MCs) has been described in which viral dsRNA binding to TLR3 can trigger the release of IFN- α and β , various chemokines and cytokines such as CCL3, CXCL8, TNF, and IL-1 β , and a pro-inflammatory lipid mediator, cysLTs [ 4 ].…”