Non-Essential Role for TLR2 and Its Signaling Adaptor Mal/TIRAP in Preserving Normal Lung Architecture in Mice

Ruwanpura, Saleela; McLeod, Louise; Lilja, Andrew; Brooks, Gavin D.; Dousha, Lovisa; Seow, Huei Jiunn; Bozinovski, Steven; Vlahos, Ross; Hertzog, Paul J.; Anderson, Gary P.; Jenkins, Brendan J.

doi:10.1371/journal.pone.0078095

Cited by 8 publications

(7 citation statements)

References 52 publications

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“…In support of our previous report, in which we detected increased Nox3 in TLR4 -/mice, Ruwanpura et al reported that elevated oxidative protein carbonylation levels and increased numbers of alveolar cell apoptosis were detected in TLR4 -/mice, along with upregulation of Nox3 mRNA expression (23). Our studies of double TLR4 -/-/Nox3 -/mice demonstrate for the first time in vivo that Nox3 mediates, at least in part, the lung injury phenotype of TLR4 -/mice.…”

Section: Discussionsupporting

confidence: 91%

An Endothelial Hsp70-TLR4 Axis Limits Nox3 Expression and Protects Against Oxidant Injury in Lungs

Zhang

Shan

Srivastava

et al. 2016

Antioxidants & Redox Signaling

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Section: Discussionsupporting

confidence: 91%

An Endothelial Hsp70-TLR4 Axis Limits Nox3 Expression and Protects Against Oxidant Injury in Lungs

Zhang

Shan

Srivastava

et al. 2016

Antioxidants & Redox Signaling

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“…Aberrant expression of RAGE in the lung, irrespective of whether it is increased or decreased, is associated with abnormal lung morphogenesis, airspace enlargement and the development of emphysema‐like pathology 7,38‐42 . Moreover, TLR4 −/− mice develop emphysema as they age, largely as a result of increased oxidant generation and elastolytic activity 43,44 . Thus, collectively, the current evidence indicates important roles for RAGE and TLR4 in maintaining lung homeostasis, structure and function and further emphasizes the need to better understand the role of these receptors in the lung, both in health and disease.…”

Section: Discussionmentioning

confidence: 91%

“…7,[38][39][40][41][42] Moreover, TLR4 −/− mice develop emphysema as they age, largely as a result of increased oxidant generation and elastolytic activity. 43,44 Thus, collectively, the current evidence indicates important roles for RAGE and TLR4 in maintaining lung homeostasis, structure and function and further emphasizes the need to better understand the role of these receptors in the lung, both in health and disease.…”

Section: Discussionmentioning

confidence: 98%

RAGE and TLR4 differentially regulate airway hyperresponsiveness: Implications for COPD

Allam

Faiz

Lam

et al. 2020

Allergy

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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.

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“…Given that TLR2 and TLR4 have been previously shown to play roles in mediating pulmonary oxidative stress (32,61,83,109), we also profiled the mRNA expression of NADPH oxidase (Nox)1, Nox2, Nox3, Nox4, NAD(P)H quinone dehydrogenase (Nqo)1, nuclear factor (erythroid-derived 2)-like-2 factor (Nrf2), glutamate-cysteine ligase catalytic subunit (Gclc), glutathione peroxidase (Gpx)2, heme oxygenase (Hmox)1 and glutathione Stransferase pi (Gstp)1 ( Figure 6J-S). CS exposure induced the expression of Nox2 ( Figure 6K) and suppressed Gstp1 ( Figure 6S), whilst other genes were not altered in Tlr2 -/or Tlr4 -/mice compared to WT controls.…”

Section: Cs-induced Pulmonary Inflammation Was Largely Unaltered In Tmentioning

confidence: 99%

Toll-like receptor 2 and 4 have Opposing Roles in the Pathogenesis of Cigarette Smoke-induced Chronic Obstructive Pulmonary Disease

Haw

Starkey

Pavlidis

et al. 2017

American Journal of Physiology-Lung Cellular and Molecular Phys

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Chronic obstructive pulmonary disease (COPD) is the third leading cause of morbidity and death and imposes major socioeconomic burdens globally. It is a progressive and disabling condition that severely impairs breathing and lung function. There is a lack of effective treatments for COPD, which is a direct consequence of the poor understanding of the underlying mechanisms involved in driving the pathogenesis of the disease. Toll-like receptor (TLR)2 and TLR4 are implicated in chronic respiratory diseases, including COPD, asthma and pulmonary fibrosis. However, their roles in the pathogenesis of COPD are controversial and conflicting evidence exists. In the current study, we investigated the role of TLR2 and TLR4 using a model of cigarette smoke (CS)-induced experimental COPD that recapitulates the hallmark features of human disease. TLR2, TLR4, and associated coreceptor mRNA expression was increased in the airways in both experimental and human COPD. Compared with wild-type (WT) mice, CS-induced pulmonary inflammation was unaltered in TLR2-deficient ( Tlr2) and TLR4-deficient ( Tlr4) mice. CS-induced airway fibrosis, characterized by increased collagen deposition around small airways, was not altered in Tlr2 mice but was attenuated in Tlr4 mice compared with CS-exposed WT controls. However, Tlr2 mice had increased CS-induced emphysema-like alveolar enlargement, apoptosis, and impaired lung function, while these features were reduced in Tlr4 mice compared with CS-exposed WT controls. Taken together, these data highlight the complex roles of TLRs in the pathogenesis of COPD and suggest that activation of TLR2 and/or inhibition of TLR4 may be novel therapeutic strategies for the treatment of COPD.

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Non-Essential Role for TLR2 and Its Signaling Adaptor Mal/TIRAP in Preserving Normal Lung Architecture in Mice

Cited by 8 publications

References 52 publications

An Endothelial Hsp70-TLR4 Axis Limits Nox3 Expression and Protects Against Oxidant Injury in Lungs

An Endothelial Hsp70-TLR4 Axis Limits Nox3 Expression and Protects Against Oxidant Injury in Lungs

RAGE and TLR4 differentially regulate airway hyperresponsiveness: Implications for COPD

Toll-like receptor 2 and 4 have Opposing Roles in the Pathogenesis of Cigarette Smoke-induced Chronic Obstructive Pulmonary Disease

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