Secretory Autophagosomes from Alveolar Macrophages Exacerbate Acute Respiratory Distress Syndrome by Releasing IL-1β

Xu, Xinyi; Liu, Xu; Dong, Xuecheng; Qiu, Haibo; Yang, Yi; Liu, Ling

doi:10.2147/jir.s344857

Cited by 11 publications

(14 citation statements)

References 45 publications

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“…The production of pro-inflammatory cytokines is an important feature of ARDS, and therapeutic targeting of these cytokines can ameliorate ARDS progression ( Rubenfeld et al., 2005 ; Vanden Berghe et al., 2014 ). We demonstrated that AM-derived SAPs contributed to the overwhelming inflammation of ARDS via secretion of IL-1β ( Xu et al., 2022 ). Thus, it is reasonable to assume that the MiR-199a-3p antagomir could have a protective function by modulating SAP secretion, which implies that the MiR-199a-3p antagomir may be a curative candidate for the treatment of ARDS.…”

Section: Discussionmentioning

confidence: 99%

“…We collected secretory autophagosomes in accordance with the methods published previously ( Xu et al., 2022 ). In order to remove debris, the cell culture supernatants or bronchoalveolar lavage fluid samples were acquired and centrifuged at 400× g for 5 min at first; then, we collected the supernatants for centrifugation of 12,000× g for 30 min.…”

Section: Methodsmentioning

confidence: 99%

“…We previously identified a novel type of vesicles from AMs, which could be characterized as double-membrane vesicles with the expression of light chain 3 (LC3) and which could be considered as secretory autophagosomes (SAPs). We found that AM-derived secretory autophagosomes could amplify the inflammation and aggravate the lung injury of ARDS, and therefore regulating SAP secretion would significantly alleviate the inflammatory and pathological injury of ARDS ( Xu et al., 2022 ). However, the participation of microRNAs in regulating AM-derived SAP secretion remains to be clearly defined.…”

Section: Introductionmentioning

confidence: 99%

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MiR-199a-3p-regulated alveolar macrophage-derived secretory autophagosomes exacerbate lipopolysaccharide-induced acute respiratory distress syndrome

Liu

Dong

et al. 2022

Front. Cell. Infect. Microbiol.

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PurposeAcute respiratory distress syndrome (ARDS) is a prevalent illness in intensive care units. Extracellular vesicles and particles released from activated alveolar macrophages (AMs) assist in ARDS lung injury and the inflammatory process through mechanisms that are unclear. This study investigated the role of AM-derived secretory autophagosomes (SAPs) in lung injury and microRNA (MiR)-199a-3p-regulated inflammation associated with ARDS in vitro and in a murine model.MethodsThe ARDS model in mouse was established by intratracheal LPS lipopolysaccharide (LPS) injection. The agomirs or antagomirs of MiR-199a-3p were injected into the caudal vein to figure out whether MiR-199a-3p could influence ARDS inflammation and lung injury, whereas the mimics or inhibitors of MiR-199a-3p, siRNA of Rab8a, or PAK4 inhibitor were transfected or applied to RAW264.7 cells to evaluate the mechanism of SAP release. Culture supernatants of RAW264.7 cells treated with LPS or bronchoalveolar lavage fluid from mice were collected for the isolation of SAPs.ResultsWe found that MiR-199a-3p was over-expressed in the lungs of ARDS mice. The MiR-199a-3p antagomir alleviated, whereas the MiR-199a-3p agomir exacerbated LPS-induced inflammation in mice by promoting AM-derived SAP secretion. In addition, MiR-199a-3p over-expression exacerbated LPS-induced ARDS via activating Rab8a, and Rab8a silencing significantly suppressed the promoting influence of the MiR-199a-3p mimic on SAP secretion. Furthermore, MiR-199a-3p mimic activated Rab8a by directly inhibiting PAK4 expression.ConclusionThe novel finding of this study is that MiR-199a-3p participated in the regulation of SAP secretion and the inflammatory process via targeting of PAK4/Rab8a, and is a potential therapeutic candidate for ARDS treatment.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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MiR-199a-3p-regulated alveolar macrophage-derived secretory autophagosomes exacerbate lipopolysaccharide-induced acute respiratory distress syndrome

Liu

Dong

et al. 2022

Front. Cell. Infect. Microbiol.

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“…Monocytes/macrophages are the predominant cell type that secretes IL-1β. In pulmonary inflammatory diseases such as lung infection, 32 pulmonary fibrosis, 33 asthma, 34 and ALI, 35 a high number of IL-1β produced by AMs correlates strongly with disease severity. We found that iNOS and IL-1β mRNA and protein expression were extremely high in the LPS-treated AMs, and the knockdown of C/EBPβ significantly altered this phenomenon.…”

Section: Discussionmentioning

confidence: 99%

C/EBPβ Promotes LPS-Induced IL-1β Transcription and Secretion in Alveolar Macrophages via NOD2 Signaling

Luo¹,

Ge²,

Wen³

et al. 2022

JIR

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Objective C/EBPβ, a crucial transcription factor, regulates innate immunity and inflammatory responses. However, the role played by C/EBPβ in alveolar macrophage (AM) inflammatory responses remains unknown. This study aimed to investigate the role and mechanism of C/EBPβ in alveolar macrophages (AMs) from the transcriptional level and to search for natural compounds targeting C/EBPβ. Methods Rat AMs were infected with Lv-sh-C/EBPβ and treated with LPS, and the expression levels of iNOS, TNF-α, IL-6, and IL-1β were measured by RT-qPCR, Western blotting, and ELISA. Mechanistically, transcriptome sequencing (RNA-seq) revealed changes in gene expression patterns in AMs after LPS stimulation and C/EBPβ knockdown. Functional enrichment analyses and rescue experiments identified and validated inflammation-associated cell signaling pathways regulated by C/EBPβ. Furthermore, virtual screening was used to search for natural compounds that inhibit C/EBPβ with the structure of helenalin as a reference. Results Following stimulation with LPS, AMs exhibited an increased expression of C/EBPβ. C/EBPβ knockdown significantly decreased the expression levels of inflammatory mediators. A total of 374 differentially expressed genes (DEGs) were identified between LPS-stimulated C/EBPβ knockdown and negative control cells. The NOD-like receptor signaling may be a key target for C/EBPβ, according to functional enrichment analyses of the DEGs. Further experiments showed that the muramyl dipeptide (MDP, NOD2 agonist) reversed the downregulation of inflammatory mediators and the NF-κB pathway caused by the C/EBPβ knockdown. The virtual screening revealed that N-caffeoyltryptophan, orilotimod, and petasiphenone have comparable pharmacological properties to helenalin (a known C/EBPβ inhibitor) and demonstrate a great binding capacity to C/EBPβ. Conclusion Ablation of C/EBPβ may attenuate LPS-induced inflammatory damage in AMs by inhibiting the NOD2 receptor signaling pathway. Three natural compounds, N-caffeoyltryptophan, orilotimod, and petasiphenone, may be potential C/EBPβ inhibitors.

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“…An interesting aspect is the role of secretory autophagosomes (SAPs), double-membrane vesicles which can be regarded as EVs and exacerbate lung injury. SAPs were secreted by LPS-treated AMs and their intratracheal administration induced lung injury through IL-1β secretion [ 111 ]. EVs extracted from BALF of mice treated with intratracheal LPS showed an increased expression of miRNA-466.…”

Section: Role Of Extracellular Vesicles In Sepsis-associated Ardsmentioning

confidence: 99%

Dual Role of Extracellular Vesicles in Sepsis-Associated Kidney and Lung Injury

et al. 2022

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Extracellular vesicles form a complex intercellular communication network, shuttling a variety of proteins, lipids, and nucleic acids, including regulatory RNAs, such as microRNAs. Transfer of these molecules to target cells allows for the modulation of sets of genes and mediates multiple paracrine and endocrine actions. EVs exert broad pro-inflammatory, pro-oxidant, and pro-apoptotic effects in sepsis, mediating microvascular dysfunction and multiple organ damage. This deleterious role is well documented in sepsis-associated acute kidney injury and acute respiratory distress syndrome. On the other hand, protective effects of stem cell-derived extracellular vesicles have been reported in experimental models of sepsis. Stem cell-derived extracellular vesicles recapitulate beneficial cytoprotective, regenerative, and immunomodulatory properties of parental cells and have shown therapeutic effects in experimental models of sepsis with kidney and lung involvement. Extracellular vesicles are also likely to play a role in deranged kidney-lung crosstalk, a hallmark of sepsis, and may be key to a better understanding of shared mechanisms underlying multiple organ dysfunction. In this review, we analyze the state-of-the-art knowledge on the dual role of EVs in sepsis-associated kidney/lung injury and repair. PubMed library was searched from inception to July 2022, using a combination of medical subject headings (MeSH) and keywords related to EVs, sepsis, acute kidney injury (AKI), acute lung injury (ALI), and acute respiratory distress syndrome (ARDS). Key findings are summarized into two sections on detrimental and beneficial mechanisms of actions of EVs in kidney and lung injury, respectively. The role of EVs in kidney-lung crosstalk is then outlined. Efforts to expand knowledge on EVs may pave the way to employ them as prognostic biomarkers or therapeutic targets to prevent or reduce organ damage in sepsis.

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Secretory Autophagosomes from Alveolar Macrophages Exacerbate Acute Respiratory Distress Syndrome by Releasing IL-1β

Cited by 11 publications

References 45 publications

MiR-199a-3p-regulated alveolar macrophage-derived secretory autophagosomes exacerbate lipopolysaccharide-induced acute respiratory distress syndrome

MiR-199a-3p-regulated alveolar macrophage-derived secretory autophagosomes exacerbate lipopolysaccharide-induced acute respiratory distress syndrome

C/EBPβ Promotes LPS-Induced IL-1β Transcription and Secretion in Alveolar Macrophages via NOD2 Signaling

Dual Role of Extracellular Vesicles in Sepsis-Associated Kidney and Lung Injury

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