Molecular Regulation of Toll-like Receptors in Asthma and COPD

Abstract

Asthma and chronic obstructive pulmonary disease (COPD) have both been historically associated with significant morbidity and financial burden. These diseases can be induced by several exogenous factors, such as pathogen-associated molecular patterns (PAMPs) (e.g., allergens and microbes). Endogenous factors, including reactive oxygen species, and damage-associated molecular patterns (DAMPs) recognized by toll-like receptors (TLRs), can also result in airway inflammation. Asthma is characterized by the dominant presence of eosinophils, mast cells, and clusters of differentiation (CD)4+ T cells in the airways, while COPD typically results in the excessive formation of neutrophils, macrophages, and CD8+ T cells in the airways. In both asthma and COPD, in the respiratory tract, TLRs are the primary proteins of interest associated with the innate and adaptive immune responses; hence, multiple treatment options targeting TLRs are being explored in an effort to reduce the severity of the symptoms of these disorders. TLR-mediated pathways for both COPD and asthma have their similarities and differences with regards to cell types and the pro-inflammatory cytotoxins present in the airway. Because of the complex TLR cascade, a variety of treatments have been used to minimize airway hypersensitivity and promote bronchodilation. Although unsuccessful at completely alleviating COPD and severe asthmatic symptoms, new studies are focused on possible targets within the TLR cascade to ameliorate airway inflammation.

The lung microbiome: the perfect culprit for COPD exacerbations?

“…Cigarette smoke exposure alters bronchial epithelium resulting in various changes in the release of inflammatory mediators involved in macrophages and neutrophil recruitment and activation [9]. The expression of toll like receptor (TLR) 2 and TLR4 is modified contributing to a potential increased susceptibility for bacterial infections [10,11].…”

Increased neutrophil expression of pattern recognition receptors during COPD exacerbations

“…Recently, we have shown that serum levels of the RAGE‐activating DAMPs HMGB1, S100A9 and LL‐37 are increased in COPD patients during exacerbation compared with stable disease . These DAMPs can activate PRRs on neutrophils to induce their recruitment …”

“…The activation of TLR2/4 induces activation and migration of neutrophils and may thus contribute to the increased airway inflammation during COPD exacerbations . Furthermore, a positive feedback loop has been described in which DAMPs not only activate TLR4, but also induce TLR4 upregulation indicating that the increased expression of TLRs may be a consequence of DAMP release . Thus, increased neutrophilic expression of TLR2 and TLR4 in combination with increased DAMP levels may contribute to DAMP‐induced neutrophilic airway inflammation during COPD exacerbations.…”

A TNFRSF14-FcɛRI-mast cell pathway contributes to development of multiple features of asthma pathology in mice

“…In this context, it has been shown that stimuli from the microenvironment can influence IgE-dependent signalling in MCs and can thereby selectively modulate MC responses, for example, through activation of MC interleukin (IL)-33 receptors (IL-33Rs), thymic stromal lymphopoietin receptors (TSLPRs) and toll-like receptors1112. IgE-dependent signalling in MCs also can be modulated by the engagement of (tumour-necrosis factor (TNF)):TNF receptor (TNFR) superfamily molecules.…”