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Toll-like receptor 2 and 4 have opposing roles in the pathogenesis of cigarette smoke-induced chronic obstructive pulmonary disease.

ABSTRACT: 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.

SUBMITTER: Haw TJ

PROVIDER: S-EPMC5866502 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Toll-like receptor 2 and 4 have opposing roles in the pathogenesis of cigarette smoke-induced chronic obstructive pulmonary disease.

Haw Tatt Jhong TJ Starkey Malcolm R MR Pavlidis Stelios S Fricker Michael M Arthurs Anya L AL Nair Prema M PM Liu Gang G Hanish Irwan I Kim Richard Y RY Foster Paul S PS Horvat Jay C JC Adcock Ian M IM Hansbro Philip M PM

American journal of physiology. Lung cellular and molecular physiology 20171012 2

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 ...[more]

PMID: 29025711

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Project description:AimsRecent studies have shown that cigarette smoke (CS)-induced oxidative stress impairs autophagy, resulting in aggresome-formation that correlates with severity of chronic obstructive pulmonary disease (COPD)-emphysema, although the specific step in autophagy pathway that is impaired is unknown. Hence, in this study, we aimed to evaluate the role of master autophagy transcription factor EB (TFEB) in CS-induced COPD-emphysema pathogenesis.ResultsWe first observed that TFEB accumulates in perinuclear spaces as aggresome-bodies in COPD lung tissues of tobacco smokers and severe emphysema subjects, compared with non-emphysema or nonsmoker controls. Next, Beas2b cells and C57BL/6 mice were exposed to either cigarette smoke extract (CSE) or subchronic-CS (sc-CS), followed by treatment with potent TFEB-inducing drug, gemfibrozil (GEM, or fisetin as an alternate), to experimentally verify the role of TFEB in COPD. Our in vitro results indicate that GEM/fisetin-mediated TFEB induction significantly (p?<?0.05) decreases CSE-induced autophagy-impairment (Ub/LC3B reporter and autophagy flux assay) and resulting aggresome-formation (Ub/p62 coexpression/accumulation; immunoblotting and staining) by controlling reactive oxygen species (ROS) activity. Intriguingly, we observed that CS induces TFEB accumulation in the insoluble protein fractions of Beas2b cells, which shows a partial rescue with GEM treatment. Moreover, TFEB knockdown induces oxidative stress, autophagy-impairment, and senescence, which can all be mitigated by GEM-mediated TFEB induction. Finally, in vivo studies were used to verify that CS-induced autophagy-impairment (increased Ub, p62, and valosin-containing protein in the insoluble protein fractions of lung/cell lysates), inflammation (interleukin-6 [IL-6] levels in bronchoalveolar lavage fluid and iNOS expression in lung sections), apoptosis (caspase-3/7), and resulting emphysema (hematoxylin and eosin [H&E]) can be controlled by GEM-mediated TFEB induction (p?<?0.05).InnovationCS exposure impairs autophagy in COPD-emphysema by inducing perinuclear localization of master autophagy regulator, TFEB, to aggresome-bodies.ConclusionTFEB-inducing drug(s) can control CS-induced TFEB/autophagy-impairment and COPD-emphysema pathogenesis. Antioxid. Redox Signal. 27, 150-167.

Dataset Information

Toll-like receptor 2 and 4 have opposing roles in the pathogenesis of cigarette smoke-induced chronic obstructive pulmonary disease.

Publications

Toll-like receptor 2 and 4 have opposing roles in the pathogenesis of cigarette smoke-induced chronic obstructive pulmonary disease.

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