RAGE and TLR4 differentially regulate airway hyperresponsiveness: Implications for COPD

Abstract

Background The receptor for advanced glycation end products (RAGE) and Toll‐like receptor 4 (TLR4) is implicated in COPD. Although these receptors share common ligands and signalling pathways, it is not known whether they act in concert to drive pathological processes in COPD. We examined the impact of RAGE and/or TLR4 gene deficiency in a mouse model of COPD and also determined whether expression of these receptors correlates with airway neutrophilia and airway hyperresponsiveness (AHR) in COPD patients. Methods We measured airway inflammation and AHR in wild‐type, RAGE−/−, TLR4−/− and TLR4−/−RAGE−/− mice following acute exposure to cigarette smoke (CS). We also examined the impact of smoking status on AGER (encodes RAGE) and TLR4 bronchial gene expression in patients with and without COPD. Finally, we determined whether expression of these receptors correlates with airway neutrophilia and AHR in COPD patients. Results RAGE−/− mice were protected against CS‐induced neutrophilia and AHR. In contrast, TLR4−/− mice were not protected against CS‐induced neutrophilia and had more severe CS‐induced AHR. TLR4−/−RAGE−/− mice were not protected against CS‐induced neutrophilia but were partially protected against CS‐induced mediator release and AHR. Current smoking was associated with significantly lower AGER and TLR4 expression irrespective of COPD status, possibly reflecting negative feedback regulation. However, consistent with preclinical findings, AGER expression correlated with higher sputum neutrophil counts and more severe AHR in COPD patients. TLR4 expression did not correlate with neutrophilic inflammation or AHR. Conclusions Inhibition of RAGE but not TLR4 signalling may protect against airway neutrophilia and AHR in COPD.

Binding of RAGE (AAs 362-367) and RIPK1 induces cognitive deficit in chronic hyperglycemia-derived neuroinflammation

“…Taken together, this provides reasonable explanation that RAGE plays an exacerbating role in the pathogenesis of cognitive disorder in diabetes, as microglia activation and neuronal damage occur almost simultaneously. These ndings are consistent with the evidence that transmembrane receptors may directly interaction with various protein in different cells to induce diverse disease processes [39]. It is worth noting that study focusing on the accurate domain by which RIPK1 interaction with RAGE requires future clari cation.…”

Cigarette Smoke Condensate Exposure Induces Receptor for Advanced Glycation End-Products (RAGE)-Dependent Sterile Inflammation in Amniotic Epithelial Cells

“…However, Allam et al demonstrated that RAGE and TLR4 differentially regulate airway responsiveness to cigarette smoke (CS). Indeed, the authors used RAGE and TLR4 knockout mice and found that only RAGE deletion procured protection against CS-induced neutrophils and airway responsiveness [ 43 ]. In our amniotic context, we tested at the beginning of the project the impact of CSC on TLR4 expression and found that there is no induction (ratio 1.1 by qRT-PCR, Supplementary Data S1, See Supplementary Files ) excluding the TLR4 hypothesis.…”

The Role of Epithelial Damage in the Pulmonary Immune Response

“…Stimulation of PRRs via PAMPs/DAMPs is a critical component of the innate immune response to damage, causing activation of numerous proinflammatory pathways involved in the immune response to pathogens as well as contributing to disease pathogenesis of non-infectious lung diseases. For example, TLR4 and the receptor for advanced glycation end-products (RAGE) are widely expressed throughout the respiratory epithelium, where they have pivotal roles in triggering the proinflammatory response [22,23].…”