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METTL14 contributes to acute lung injury by stabilizing NLRP3 expression in an IGF2BP2-dependent manner.

ABSTRACT: Acute lung injury (ALI) as well as its more severe form, acute respiratory distress syndrome (ARDS), frequently leads to an uncontrolled inflammatory response. N⁶-methyladenosine (m⁶A) modification was associated with the progression of several inflammatory diseases. However, the role of methyltransferase-like 14 (METTL14)-mediated m⁶A methylation in ALI/ARDS remains unclear. Here, we reported an increase in overall expression levels of m⁶A and METTL14 in circulating monocyte-derived macrophages recruited to the lung following ALI, which is correlated with the severity of lung injury. We further demonstrated the critical function of METTL14 in activating NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome in vitro and in mouse models of ALI/ARDS, and validated NLRP3 as the downstream target of METTL14 by the m⁶A RNA immunoprecipitation (MeRIP) and RIP assays. Mechanistically, METTL14-methylated NLRP3 transcripts were subsequently recognized by insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2), an m⁶A reader, which stabilized NLRP3 mRNA. Furthermore, we observed that IGF2BP2 knockdown diminished LPS-induced ALI in mice by downregulating NLRP3 expression. In summation, our study revealed that the molecular mechanism underlying the pathogenesis of ALI/ARDS involves METTL14-mediated activation of NLRP3 inflammasome in an IGF2BP2 dependent manner, thereby demonstrating the potential of METTL14 and IGF2BP2 as promising biomarkers and therapeutic targets for ALI/ARDS treatment.

SUBMITTER: Cao F

PROVIDER: S-EPMC10787837 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature

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METTL14 contributes to acute lung injury by stabilizing NLRP3 expression in an IGF2BP2-dependent manner.

Cao Fei F Chen Guojun G Xu Yixin Y Wang Xintong X Tang Xiaole X Zhang Wenyu W Song Xiong X Yang Xiaohua X Zeng Weian W Xie Jingdun J

Cell death & disease 20240113 1

Acute lung injury (ALI) as well as its more severe form, acute respiratory distress syndrome (ARDS), frequently leads to an uncontrolled inflammatory response. N6-methyladenosine (m6A) modification was associated with the progression of several inflammatory diseases. However, the role of methyltransferase-like 14 (METTL14)-mediated m6A methylation in ALI/ARDS remains unclear. Here, we reported an increase in overall expression levels of m6A and METTL14 ...[more]

PMID: 38218935

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Project description:BackgroundAcute respiratory distress syndrome (ARDS) is a common cause of respiratory failure in many critically ill patients. Although inflammasome activation plays an important role in the induction of acute lung injury (ALI) and ARDS, the regulatory mechanism of this process is still unclear. When cells are stimulated by inflammation, the integrity and physiological function of mitochondria play a crucial part in pyroptosis. However, the underlying mechanisms and function of mitochondrial proteins in the process of pyroptosis are largely not yet known. Here, we identified the 18-kDa translocator protein (TSPO), a mitochondrial outer membrane protein, as an important mediator regulating nucleotide-binding domain, leucine-rich repeat, and pyrin domain-containing protein 3 (NLRP3) inflammasome activation in macrophages during ALI.MethodsTSPO gene knockout (KO) and lipopolysaccharide (LPS)-induced ALI/ARDS mouse models were employed to investigate the biological role of TSPO in the pathogenesis of ARDS. Murine macrophages were used to further characterize the effect of TSPO on the NLRP3 inflammasome pathway. Activation of NLRP3 inflammasome was preformed through LPS + adenosine triphosphate (ATP) co-stimulation, followed by detection of mitochondrial membrane potential, reactive oxygen species (ROS) production, and cell death to evaluate the potential biological function of TSPO. Comparisons between two groups were performed with a two-sided unpaired t -test.ResultsTSPO- KO mice exhibited more severe pulmonary inflammation in response to LPS-induced ALI. TSPO deficiency resulted in enhanced activation of the NLRP3 inflammasome pathway, promoting more proinflammatory cytokine production of macrophages in LPS-injured lung tissue, including interleukin (IL)-1β, IL-18, and macrophage inflammatory protein (MIP)-2. Mitochondria in TSPO -KO macrophages tended to depolarize in response to cellular stress. The increased production of mitochondrial damage-associated molecular pattern led to enhanced mitochondrial membrane depolarization and pyroptosis in TSPO -KO cells.ConclusionTSPO may be the key regulator of cellular pyroptosis, and it plays a vital protective role in ARDS occurrence and development.

Project description:Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are common and devastating clinical disorders with high mortality and no specific therapy. An excessive inflammatory response results in the progression of ALI/ARDS, and the NLRP3 inflammasome is a key participant in inflammation. Erythropoietin (EPO), which is clinically used for anemia, reportedly exerts pleiotropic effects in ALI. However, whether EPO could protect against lipopolysaccharide (LPS)-induced ALI by regulating the NLRP3 inflammasome and its underlying mechanisms remain poorly elucidated. This study aimed to explore whether the therapeutic effects of EPO rely on the suppression of the NLRP3 inflammasome and the specific mechanisms in an LPS-induced ALI mouse model. ALI was induced in C57BL/6 mice by intraperitoneal (i.p.) injection of LPS (15 mg/kg). EPO was administered intraperitoneally at 5 U/g after LPS challenge. The mice were sacrificed 8 h later. Our findings indicated that application of EPO markedly diminished LPS-induced lung injury by restoring histopathological changes, lessened lung wet/dry (W/D) ratio, protein concentrations in bronchoalveolar lavage fluid (BALF) and myeloperoxidase (MPO) levels. Meanwhile, EPO evidently decreased interleukin-1? (IL-1?) and interleukin-18 (IL-18) secretion, the expression of NLRP3 inflammasome components including pro-IL-1?, NLRP3, and cleaved caspase-1 as well as phosphorylation of nuclear factor-?B (NF-?B) p65, which may be associated with activation of EPO receptor (EPOR), phosphorylation of Janus-tyrosine kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3). However, all the beneficial effects of EPO on ALI and modulation NLRP3 inflammasome were remarkably abrogated by the inhibition of EPOR/JAK2/STAT3 pathway and knockout (KO) of NLRP3 gene. Taken together, this study indicates that EPO can effectively attenuate LPS-induced lung injury in mice by suppressing the NLRP3 inflammasome, which is dependent upon activation of EPOR/JAK2/STAT3 signaling and inhibition of the NF-?B pathway.

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METTL14 contributes to acute lung injury by stabilizing NLRP3 expression in an IGF2BP2-dependent manner.

Publications

METTL14 contributes to acute lung injury by stabilizing NLRP3 expression in an IGF2BP2-dependent manner.

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