Autophagy in pulmonary macrophages mediates lung inflammatory injury via NLRP3 inflammasome activation during mechanical ventilation

The inflammatory response is a primary mechanism in the pathogenesis of ventilator-induced lung injury. Autophagy is an essential, homeostatic process by which cells break down their own components. We explored the role of autophagy in the mechanisms of mechanical ventilation-induced lung inflammatory injury. Mice were subjected to low (7 ml/kg) or high (28 ml/kg) tidal volume ventilation for 2 h. Bone marrow-derived macrophages transfected with a scrambled or autophagy-related protein 5 small interfering RNA were administered to alveolar macrophage-depleted mice via a jugular venous cannula 30 min before the start of the ventilation protocol. In some experiments, mice were ventilated in the absence and presence of autophagy inhibitors 3-methyladenine (15 mg/kg ip) or trichostatin A (1 mg/kg ip). Mechanical ventilation with a high tidal volume caused rapid (within minutes) activation of autophagy in the lung. Conventional transmission electron microscopic examination of lung sections showed that mechanical ventilation-induced autophagy activation mainly occurred in lung macrophages. Autophagy activation in the lungs during mechanical ventilation was dramatically attenuated in alveolar macrophage-depleted mice. Selective silencing of autophagy-related protein 5 in lung macrophages abolished mechanical ventilation-induced nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome activation and lung inflammatory injury. Pharmacological inhibition of autophagy also significantly attenuated the inflammatory responses caused by lung hyperinflation. The activation of autophagy in macrophages mediates early lung inflammation during mechanical ventilation via NLRP3 inflammasome signaling. Inhibition of autophagy activation in lung macrophages may therefore provide a novel and promising strategy for the prevention and treatment of ventilator-induced lung injury.

Download Full-text

C1q/tumor necrosis factor‐related protein 9 protects cultured chondrocytes from IL ‐1β‐induced inflammatory injury by inhibiting NLRP3 inflammasome activation via the AdipoR1 / AMPK axis

Environmental Toxicology ◽

10.1002/tox.23452 ◽

2022 ◽

Author(s):

Bo Wang ◽

Yanqi Li ◽

Shouye Hu ◽

Kan Peng

Keyword(s):

Tumor Necrosis Factor ◽

Nlrp3 Inflammasome ◽

Tumor Necrosis ◽

Inflammasome Activation ◽

Related Protein ◽

Inflammatory Injury ◽

Nlrp3 Inflammasome Activation ◽

Necrosis Factor ◽

Cultured Chondrocytes

Download Full-text

Inhibition of IP3R/Ca2+ Dysregulation Protects Mice From Ventilator-Induced Lung Injury via Endoplasmic Reticulum and Mitochondrial Pathways

Frontiers in Immunology ◽

10.3389/fimmu.2021.729094 ◽

2021 ◽

Vol 12 ◽

Author(s):

Liu Ye ◽

Qi Zeng ◽

Maoyao Ling ◽

Riliang Ma ◽

Haishao Chen ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Lung Injury ◽

Er Stress ◽

Mitochondrial Dysfunction ◽

Nlrp3 Inflammasome ◽

Inflammatory Responses ◽

Inflammasome Activation ◽

Dependent Manner ◽

Ventilator Induced Lung Injury ◽

Nlrp3 Inflammasome Activation

RationaleDisruption of intracellular calcium (Ca2+) homeostasis is implicated in inflammatory responses. Here we investigated endoplasmic reticulum (ER) Ca2+ efflux through the Inositol 1,4,5-trisphosphate receptor (IP3R) as a potential mechanism of inflammatory pathophysiology in a ventilator-induced lung injury (VILI) mouse model.MethodsC57BL/6 mice were exposed to mechanical ventilation using high tidal volume (HTV). Mice were pretreated with the IP3R agonist carbachol, IP3R inhibitor 2-aminoethoxydiphenyl borate (2-APB) or the Ca2+ chelator BAPTA-AM. Lung tissues and bronchoalveolar lavage fluid (BALF) were collected to measure Ca2+ concentrations, inflammatory responses and mRNA/protein expression associated with ER stress, NLRP3 inflammasome activation and inflammation. Analyses were conducted in concert with cultured murine lung cell lines.ResultsLungs from mice subjected to HTV displayed upregulated IP3R expression in ER and mitochondrial-associated-membranes (MAMs), with enhanced formation of MAMs. Moreover, HTV disrupted Ca2+ homeostasis, with increased flux from the ER to the cytoplasm and mitochondria. Administration of carbachol aggravated HTV-induced lung injury and inflammation while pretreatment with 2-APB or BAPTA-AM largely prevented these effects. HTV activated the IRE1α and PERK arms of the ER stress signaling response and induced mitochondrial dysfunction-NLRP3 inflammasome activation in an IP3R-dependent manner. Similarly, disruption of IP3R/Ca2+ in MLE12 and RAW264.7 cells using carbachol lead to inflammatory responses, and stimulated ER stress and mitochondrial dysfunction.ConclusionIncrease in IP3R-mediated Ca2+ release is involved in the inflammatory pathophysiology of VILI via ER stress and mitochondrial dysfunction. Antagonizing IP3R/Ca2+ and/or maintaining Ca2+ homeostasis in lung tissue represents a prospective treatment approach for VILI.

Download Full-text

Ventilator-induced lung injury is alleviated by inhibiting NLRP3 inflammasome activation

Molecular Immunology ◽

10.1016/j.molimm.2019.03.011 ◽

2019 ◽

Vol 111 ◽

pp. 1-10 ◽

Cited By ~ 5

Author(s):

Huan Liu ◽

Changping Gu ◽

Mengjie Liu ◽

Ge Liu ◽

Dong Wang ◽

...

Keyword(s):

Lung Injury ◽

Nlrp3 Inflammasome ◽

Inflammasome Activation ◽

Ventilator Induced Lung Injury ◽

Nlrp3 Inflammasome Activation

Download Full-text

SARS-CoV-2 N protein promotes NLRP3 inflammasome activation to induce hyperinflammation

Nature Communications ◽

10.1038/s41467-021-25015-6 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Pan Pan ◽

Miaomiao Shen ◽

Zhenyang Yu ◽

Weiwei Ge ◽

Keli Chen ◽

...

Keyword(s):

Lung Injury ◽

Nlrp3 Inflammasome ◽

Cultured Cells ◽

Inflammatory Responses ◽

Specific Inhibitor ◽

Inflammasome Activation ◽

N Protein ◽

Distinct Mechanism ◽

Nlrp3 Inflammasome Activation ◽

Proinflammatory Responses

AbstractExcessive inflammatory responses induced upon SARS-CoV-2 infection are associated with severe symptoms of COVID-19. Inflammasomes activated in response to SARS-CoV-2 infection are also associated with COVID-19 severity. Here, we show a distinct mechanism by which SARS-CoV-2 N protein promotes NLRP3 inflammasome activation to induce hyperinflammation. N protein facilitates maturation of proinflammatory cytokines and induces proinflammatory responses in cultured cells and mice. Mechanistically, N protein interacts directly with NLRP3 protein, promotes the binding of NLRP3 with ASC, and facilitates NLRP3 inflammasome assembly. More importantly, N protein aggravates lung injury, accelerates death in sepsis and acute inflammation mouse models, and promotes IL-1β and IL-6 activation in mice. Notably, N-induced lung injury and cytokine production are blocked by MCC950 (a specific inhibitor of NLRP3) and Ac-YVAD-cmk (an inhibitor of caspase-1). Therefore, this study reveals a distinct mechanism by which SARS-CoV-2 N protein promotes NLRP3 inflammasome activation and induces excessive inflammatory responses.

Download Full-text

Tetrandrine alleviates silicosis by inhibiting canonical and non-canonical NLRP3 inflammasome activation in lung macrophages

Acta Pharmacologica Sinica ◽

10.1038/s41401-021-00693-6 ◽

2021 ◽

Author(s):

Mei-yue Song ◽

Jia-xin Wang ◽

You-liang Sun ◽

Zhi-fa Han ◽

Yi-tian Zhou ◽

...

Keyword(s):

Nlrp3 Inflammasome ◽

Therapeutic Strategy ◽

Molecular Targets ◽

Mechanisms Of Action ◽

Inflammasome Activation ◽

Lung Macrophages ◽

Nlrp3 Inflammasome Activation ◽

Function Test ◽

And Control ◽

Therapeutic Administration

AbstractSilicosis caused by inhalation of silica particles leads to more than ten thousand new occupational exposure-related deaths yearly. Exacerbating this issue, there are currently few drugs reported to effectively treat silicosis. Tetrandrine is the only drug approved for silicosis treatment in China, and despite more than decades of use, its efficacy and mechanisms of action remain largely unknown. Here, in this study, we established silicosis mouse models to investigate the effectiveness of tetrandrine of early and late therapeutic administration. To this end, we used multiple cardiopulmonary function test, as well as markers for inflammation and fibrosis. Moreover, using single cell RNA sequencing and transcriptomics of lung tissue and quantitative microarray analysis of serum from silicosis and control mice, our results provide a novel description of the target pathways for tetrandrine. Specifically, we found that tetrandrine attenuated silicosis by inhibiting both the canonical and non-canonical NLRP3 inflammasome pathways in lung macrophages. Taken together, our work showed that tetrandrine yielded promising results against silicosis-associated inflammation and fibrosis and further lied the groundwork for understanding its molecular targets. Our results also facilitated the wider adoption and development of tetrandirne, potentially accelerating a globally accepted therapeutic strategy for silicosis.

Download Full-text