Inhibition of TLR9-NF-κB-mediated sterile inflammation improves pressure overload-induced right ventricular dysfunction in rats

Yoshida, K; Abe, Kohtaro; Ishikawa, Mariko; Saku, Keita; Shinoda-Sakamoto, Masako; Ishikawa, Tomohito; Watanabe, Takanori; Oka, Masahiko; Sunagawa, Kenji; Tsutsui, Hiroyuki

doi:10.1093/cvr/cvy209

Cited by 22 publications

(23 citation statements)

References 39 publications

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“…Based on this information, the next analysis centered on the potential involvement of TLR-9 activation in the M. leprae-induced immune activation in these cells. For this purpose, we employed E6446, a very selective antagonist for TLR-9 used in several previous reports (21,(78)(79)(80)(81)(82). The inclusion of TLR-4 and TLR-9 ligands as negative and positive controls, respectively, in our assays reinforced the specificity of E6446 towards TLR-9.…”

Section: Discussionmentioning

confidence: 84%

TLR-9 Plays a Role in Mycobacterium leprae-Induced Innate Immune Activation of A549 Alveolar Epithelial Cells

Dias

Silva

et al. 2021

Front. Immunol.

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The respiratory tract is considered the main port of entry of Mycobacterium leprae, the causative agent of leprosy. However, the great majority of individuals exposed to the leprosy bacillus will never manifest the disease due to their capacity to develop protective immunity. Besides acting as a physical barrier, airway epithelium cells are recognized as key players by initiating a local innate immune response that orchestrates subsequent adaptive immunity to control airborne infections. However, to date, studies exploring the interaction of M. leprae with the respiratory epithelium have been scarce. In this work, the capacity of M. leprae to immune activate human alveolar epithelial cells was investigated, demonstrating that M. leprae-infected A549 cells secrete significantly increased IL-8 that is dependent on NF-κB activation. M. leprae was also able to induce IL-8 production in human primary nasal epithelial cells. M. leprae-treated A549 cells also showed higher expression levels of human β-defensin-2 (hβD-2), MCP-1, MHC-II and the co-stimulatory molecule CD80. Furthermore, the TLR-9 antagonist inhibited both the secretion of IL-8 and NF-κB activation in response to M. leprae, indicating that bacterial DNA sensing by this Toll-like receptor constitutes an important innate immune pathway activated by the pathogen. Finally, evidence is presented suggesting that extracellular DNA molecules anchored to Hlp, a histone-like protein present on the M. leprae surface, constitute major TLR-9 ligands triggering this pathway. The ability of M. leprae to immune activate respiratory epithelial cells herein demonstrated may represent a very early event during infection that could possibly be essential to the generation of a protective response.

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Section: Discussionmentioning

confidence: 84%

TLR-9 Plays a Role in Mycobacterium leprae-Induced Innate Immune Activation of A549 Alveolar Epithelial Cells

Dias

Silva

et al. 2021

Front. Immunol.

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“…In early PH, an increase in afterload induces adaptive cardiac hypertrophy to maintain RV stroke volume. However, with persistently elevated RV pressure overload, the RV dilates, which results in impaired contractility and systolic and diastolic parameters (17). We have demonstrated that administration of the anti-inflammatory P2X7R antagonist PKT100 allows sustained RV contractile performance compared with vehicle-treated bleomycin mice.…”

Section: H189 P2x7r Inhibition Improves Survival In Pulmonary Hypertensionmentioning

confidence: 89%

The novel P2X7 receptor antagonist PKT100 improves cardiac function and survival in pulmonary hypertension by direct targeting of the right ventricle

Hansen

Galougahi

Besnier

et al. 2020

American Journal of Physiology-Heart and Circulatory Physiology

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This study demonstrates the therapeutic potential for right-sided heart failure of a novel inhibitor of the P2X7 receptor (P2X7R). Inflammatory signaling and right ventricular function were improved in a mouse model of pulmonary fibrosis with secondary pulmonary hypertension when treated with this inhibitor. Importantly, survival was also improved, suggesting that this inhibitor, and other P2X7R antagonists, could be uniquely effective in right ventricle (RV)-targeted therapy in pulmonary hypertension. This addresses a major limitation of current treatment options, where the significant improvements in pulmonary pressures ultimately do not prevent mortality due to RV failure.

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“…There are few reports indicating that inhibition of NF-κB is effective in pulmonary fibrosis. However, there is no report showing a direct link between genetic blockade of NF-κB in the lungs and pulmonary fibrosis [ 34 – 36 ]. This report provides for the first time that the genetic inhibition of NF-κB in the lungs prevents the BLM-induced lung fibrosis.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of nuclear factor κB in the lungs protect bleomycin-induced lung fibrosis in mice

et al. 2022

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Background Pulmonary fibrosis is a debilitating condition with limited therapeutic avenues. The pathogenicity of pulmonary fibrosis constitutes involvement of cellular proliferation, activation, and transformational changes of fibroblast to myofibroblasts. It is a progressive lung disease and is primarily characterized by aberrant accumulation of extracellular matrix proteins in the lungs with poor prognosis. The inflammatory response in the pathogenesis of lung fibrosis is suggested because of release of several cytokines; however, the underlying mechanism remains undefined. A genetic model is the appropriate way to delineate the underlying mechanism of pulmonary fibrosis. Methods and results In this report, we have used cc-10 promoter based IκBα mutant mice (IKBM, an inhibitor of NF-κB) which were challenged with bleomycin (BLM). Compared to wild-type (WT) mice, the IKBM mice showed significant reduction in several fibrotic, vascular, and inflammatory genes. Moreover, we have identified a new set of dysregulated microRNAs (miRNAs) by miRNA array analysis in BLM-induced WT mice. Among these miRNAs, let-7a-5p and miR-503-5p were further analyzed. Our data showed that these two miRNAs were upregulated in WT-BLM and were reduced in IKBM-BLM mice. Bioinformatic analyses showed that let-7a-5p and miR-503-5p target for endothelin1 and bone morphogenic receptor 1A (BMPR1A), respectively, and were downregulated in WT-BLM mice indicating a link in pulmonary fibrosis. Conclusion We concluded that inhibition of NF-κB and modulation of let-7a-5p and miR-503-5p contribute a pivotal role in pulmonary fibrosis and may be considered as possible therapeutic target for the clinical management of lung fibrosis.

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Inhibition of TLR9-NF-κB-mediated sterile inflammation improves pressure overload-induced right ventricular dysfunction in rats

Abstract: Inhibition of TLR9-NF-κB pathway‒mediated sterile inflammation improved PAB‒induced RV dysfunction in rats. This pathway plays a major role in the progression of pressure overload‒induced RV dysfunction, and is potentially a novel therapeutic target for the disorder.

Cited by 22 publications

References 39 publications

TLR-9 Plays a Role in Mycobacterium leprae-Induced Innate Immune Activation of A549 Alveolar Epithelial Cells

TLR-9 Plays a Role in Mycobacterium leprae-Induced Innate Immune Activation of A549 Alveolar Epithelial Cells

The novel P2X7 receptor antagonist PKT100 improves cardiac function and survival in pulmonary hypertension by direct targeting of the right ventricle

Inhibition of nuclear factor κB in the lungs protect bleomycin-induced lung fibrosis in mice

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