TLR Signals in Epithelial Cells in the Nasal Cavity and Paranasal Sinuses

Abstract

The respiratory tract is constantly at risk of invasion by microorganisms such as bacteria, viruses, and fungi. In particular, the mucosal epithelium of the nasal cavity and paranasal sinuses is at the very forefront of the battles between the host and the invading pathogens. Recent studies have revealed that the epithelium not only constitutes a physical barrier but also takes an essential role in the activation of the immune system. One of the mechanisms equipped in the epithelium to fight against microorganisms is the Toll-like receptor (TLR) response. TLRs recognize common structural components of microorganisms and activate the innate immune system, resulting in the production of a plethora of cytokines and chemokines in the response against microbes. As the epithelia-derived cytokines are deeply involved in the pathogenesis of inflammatory conditions in the nasal cavity and paranasal sinuses, such as chronic rhinosinusitis (CRS) and allergic rhinitis (AR), the molecules involved in the TLR response may be utilized as therapeutic targets for these diseases. There are several differences in the TLR response between nasal and bronchial epithelial cells, and knowledge of the TLR signals in the upper airway is sparse compared to that in the lower airway. In this review, we provide recent evidence on TLR signaling in the upper airway, focusing on the expression, regulation, and responsiveness of TLRs in human nasal epithelial cells (HNECs). We also discuss how TLRs in the epithelium are involved in the pathogenesis of, and possible therapeutic targeting, for CRS and AR.

Rhinitis associated with asthma is distinct from rhinitis alone: The ARIA‐MeDALL hypothesis

“…The nasal epithelium expresses all known TLRs. 224 Variations in the 10 TLR genes have been associated with AR in several candidate gene studies and three large GWASs. A significant excess of rare variants in rhinitis patients was detected in TLR1, TLR5, TLR7, TLR9, and TLR10 225 but not in TLR8.…”

“…The nasal epithelium expresses all known TLRs 224 . Variations in the 10 TLR genes have been associated with AR in several candidate gene studies and three large GWASs.…”

The recent advances of cancer associated fibroblasts in cancer progression and therapy

“…Though precise lineage tracing study has shown the origin of fibroblasts in healthy or injured tissues, the origins and specific activation processes of CAFs are still lacking (6,7). Several cells may be predecessors of CAFs, such as normal fibroblasts (8), mesenchymal stem cells (MSCs) (9), pancreatic stellate cells (PSCs) (10), epithelial cells (11), endothelial cells (12), adipocytes (13), pericytes (14), hematopoietic stem cells (15) and cancer stem cells (CSCs) (16). The changes in the microenvironment where these precursor cells exist in may be a primary inducer of CAF transition (3).…”

“…Epithelial or endothelial cells are found to be the probable origins of CAFs through epithelial-tomesenchymal transition (EMT) or endothelial-to-mesenchymal transition (EndMT). The human nasal epithelial cells were activated and displayed CAF phenotypes such as FSP or FAP through EMT when they were exposed to matrix metalloproteinase (MMP)-9 (11). TGF-b could induce proliferating endothelial cells into fibroblast-like cells (12).…”

Metallothionein-3 is a clinical biomarker for tissue zinc levels in nasal mucosa

“…Primary human nasal epithelial cells (HNECs) were taken from the nasal mucosa of donors in a method as previously described (15)(16)(17). The cells were suspended in Bronchial Epithelial Growth Medium (BEGM, CC-3170, Lonza, Walkersville, MD, USA), supplemented with 2% Ultroser G (Pall Corporation, Port Washington, NY, USA).…”