Toll‐like receptors 2, 3 and 4 and thymic stromal lymphopoietin expression in fatal asthma

Abstract

Background Airway inflammation in asthma involves innate immune responses. Toll-like receptors (TLRs) and thymic stromal lymphopoietin (TSLP) are thought to be involved in airway inflammation, but their expression in asthmatics’ both large and small airways has not been investigated. Objective To analyze the expression of TLR2, TLR3, TLR4 and TSLP in large and small airways of asthmatics and compare their expression in smoking and nonsmoking asthmatics; to investigate whether TLR expression is associated with eosinophilic or neutrophilic airway inflammation and with Mycoplasma pneumoniae and Chlamydophila pneumoniae infection. Methods Using immunohistochemistry and image analysis, we investigated TLR2, TLR3, TLR4 and TSLP expression in large and small airways of 24 victims of fatal asthma, FA, (13 nonsmokers, 11 smokers) and 9 deceased control subjects (DCtrl). TLRs were also measured in 18 mild asthmatics (MA) and 12 healthy controls (HCtrl). Mycoplasma pneumoniae and Chlamydophila pneumoniae in autopsy lung tissue was analyzed using real-time polymerase chain reaction. Airway eosinophils and neutrophils were measured in all subjects. Results Fatal asthma patients had higher TLR2 in the epithelial and outer layers of large and small airways compared with DCtrls. Smoking asthmatics had lower TLR2 levels in the inner and outer layers of the small airways than nonsmoking asthmatics. TSLP was increased in the epithelial and outer layers of the large airways of FA. FA patients had greater TLR3 expression in the outer layer of large airways and greater TLR4 expression in the outer layer of small airways. Eosinophilic airway inflammation was associated with TLR expression in the epithelium of FA. No bacterial DNA was detected in FA or DCtrls. MA and HCtrls had only a small difference in TLR3 expression. Conclusions and Clinical Relevance Increased expression of TLR 2, 3 and 4 and TSLP in fatal asthma may contribute to the acute inflammation surrounding asthma deaths.

Thymic stromal lymphopoietin induces corticosteroid resistance in natural helper cells during airway inflammation

“…This is relevant to clinical findings that levels of TSLP in airway epithelia and lamina propria are elevated in patients with severe 22 or fatal asthma 27 . TSLP expression can be induced in bronchial epithelial cells in response to various danger signals including protease antigens such as those of the house dust mite 37 .…”

“…TSLP is especially relevant to corticosteroid resistance in inflamed airways. Bronchial epithelial cells produce TSLP and the amounts of TSLP in the lung are significantly elevated in the asthmatic airways 22,26,27 . As shown here, the inhibition of TSLP or its key signalling molecule, STAT5, can restore the sensitivity of NH cells to corticosteroids.…”

“…Previous studies have revealed the involvement of TSLP in the patients with severe asthma as well as mouse asthma models 22,26,27 . Indeed, levels of Tslp mRNA and TSLP protein are elevated in the lungs of OVA alone or OVA þ IL-33 model mice ( Supplementary Fig.…”

Involvement of Toll-Like Receptor 2 and Epidermal Growth Factor Receptor Signaling in Epithelial Expression of Airway Remodeling Factors

“…Expression of TLR2 was reported to be highly elevated in patients with asthma compared with control subjects (11). In atopic dermatitis, the skin of patients is frequently colonized by SA and other TLR2-activating bacteria, associated with Th2-biased immune activation (39).…”

“…In addition, TLR2 participates in the immune response to Mycoplasma pneumonia (7), Chlamydophila pneumonia (8), and Staphylococcus aureus (SA) (9), and it has been shown that these TLR2 ligandexpressing pathogens are associated with acute exacerbations of asthma (10). Expression of TLR2 was shown to be up-regulated in asthmatic epithelial cells and in nasal epithelial cells from patients with chronic rhinosinusitis (CRS) (11)(12)(13).…”