Toll/IL-1 domain-containing adaptor inducing IFN-β (TRIF) mediates innate immune responses in murine peritoneal mesothelial cells through TLR3 and TLR4 stimulation

Abstract

Mesothelial cells are composed of monolayer of the entire surface of serosal cavities including pleural, pericardial, and peritoneal cavity. Although mesothelial cells are known to express multiple Toll-like receptors (TLRs) which contribute to trigger innate immune responses against infections, the precise molecular mechanism remains still unclear. In the present study, we investigated the role of Toll/IL-1 domain-containing adaptor inducing IFN-β (TRIF), one of the two major TLRs-adaptor molecules, on innate immune response induced by TLR3 and TLR4 stimulation in murine peritoneal mesothelial cells (PMCs). TRIF was strongly expressed in PMCs and its deficiency led to impaired production of cytokines and chemokines by poly I:C and LPS in the cells. Activation of NF-κB or MAPKs through poly I:C and LPS stimulation was reduced in TRIF-deficient PMCs as compared to the WT cells. TRIF was also necessary for optimal nitric oxide synthesis and gene expression of inducible nitric oxide synthase (iNOS) and IFN-β in PMCs in response to poly I:C and LPS. Furthermore, both Escherichia coli and Pseudomonas aeruginosa induced high level of IL-6, CXCL1, and CCL2 production in PMCs, which was significantly impaired by TRIF deficiency. These results demonstrated that TRIF is required for optimal activation of innate immune responses in mesothelial cells against microbial infections.

The Peritoneum: Beyond the Tissue – A Review

“…Kato et al (2004) demonstrated constituent expression of Toll-like receptors (TLR) 1-6, CD14, and MD-2 (required for TLR-4 signal transduction) ( Kato et al, 2004 ). Other authors have reached similar results, proving expression of TLR-1 ( Colmont et al, 2011 ), TLR-3 and TLR-2 ( Park et al, 2007 ; Colmont et al, 2011 ; Hwang et al, 2016 ), TLR-4 ( Park et al, 2007 ; Colmont et al, 2011 ; Wang J. et al, 2013 ; Hwang et al, 2016 ), TLR-6 ( Colmont et al, 2011 ), and TLR-5 ( Park et al, 2007 ; Colmont et al, 2011 ). Other receptors like nucleotide-binding oligomerization domain (Nod)-1 and Nod-2 ( Park et al, 2007 ), and AGE receptors (RAGE) ( Boulanger et al, 2002 ) have been identified.…”

Synergy of TLR3 and 7 ligands significantly enhances function of DCs to present inactivated PRRSV antigen through TRIF/MyD88-NF-κB signaling pathway

“…NF-κB also plays an essential role in innate immune response and many signaling pathways are associated with NF-κB 33 36 37 38 . In previous studies, TRIF mediated innate immune responses in peritoneal mesothelial cells through TLR3 and TLR4 stimulation via activation of NF-κB or MAPKs 39 . Hepatitis C virus NS3 mediated microglial inflammation via TLR2/TLR6-MyD88/NF-κB pathway 40 .…”

Toll-Like Receptor 3–TRIF Pathway Activation by Neospora caninum RNA Enhances Infection Control in Mice

“…Previous work indicated that inducible nitric oxide synthase (iNOS) (nitric oxide synthase 2) is absent and NO synthesis is totally impaired in TRIF-deficient murine peritoneal cells stimulated with poly(I·C) or LPS (22). There is also evidence that TRIF participates, not only in NO production, but also in the induction of reactive oxygen species (ROS) by macrophages via TLR3 (23).…”

“…Regarding the ability of the TLR3-TRIF pathway to induce IFN-␣ and IFN-␤, here, we have confirmed this mechanism in the Neospora model. Many examples of this induction may be found in the literature: in a study that used mesothelial cells, which act as a protective barrier against invasive pathogens, it was observed that stimulation with poly(I·C), a TLR3 agonist, induced the expression of IFN-␤ mRNA in WT cells; however, this induction was significantly reduced in TRIF-deficient cells (22). In other infection models, such as the bacteria Listeria monocytogenes and Chlamydia muridarum, it has been observed that macrophages deficient in TRIF also present impaired IFN-␤ expression, demonstrating again the strict relationship of the adapter molecule to the cytokine (25,26).…”