Monocyte-derived macrophages(MoMacs)are the most important effector cells that cause pulmonary fibrosis.However,the characteristics of MoMac differentiation in silicosis and the mechanisms by which MoMacs affect the p...Monocyte-derived macrophages(MoMacs)are the most important effector cells that cause pulmonary fibrosis.However,the characteristics of MoMac differentiation in silicosis and the mechanisms by which MoMacs affect the progression of pulmonary fibrosis remain unclear.Integration of single-cell and spatial transcriptomic analyses revealed that the silicosis niche was occupied by a subset of MoMacs,identified as Spp1hiMacs,which remain in an immature transitional state of differentiation during silicosis.This study investigated the mechanistic foundations of mitochondrial damage induced by the lipoprotein-associated phospholipase A2(Lp-PLA2,encoded by Pla2g7)–acyl-CoA:lysocardiolipin acyltransferase-1(ALCAT1)–cardiolipin(CL)signaling pathway,which interferes with Spp1hiMac differentiation.We demonstrated that in SiO_(2)-induced MoMacs,Lp-PLA2 induces abnormal CL acylation through the activation of ALCAT1,resulting in impaired mitochondrial localization of PINK1 and LC3B and mitochondrial autophagy defects.Simultaneously,lysosomal dysfunction causes the release of the lysosomal protein cathepsin B into the cytoplasm,which involves M1 and M2 macrophage polarization and the activation of proinflammatory and profibrotic pathways.Furthermore,we assessed the efficacy of the Lp-PLA2 inhibitor darapladib in ameliorating silica-induced pulmonary fibrosis in a murine model.Our findings enhance our understanding of silicosis pathogenesis and offer promising opportunities for developing targeted therapies to mitigate fibrotic progression and maintain lung function in affected individuals.展开更多
Genomic datasets and the tools to analyze them have proliferated at an astonishing rate.However,such tools are often poorly integrated with each other:each program typically produces its own custom output in a variety...Genomic datasets and the tools to analyze them have proliferated at an astonishing rate.However,such tools are often poorly integrated with each other:each program typically produces its own custom output in a variety of non-standard file formats.Here we present glbase,a framework that uses a flexible set of descriptors that can quickly parse non-binary data files.glbase includes many functions to intersect two lists of data,including operations on genomic interval data and support for the efficient random access to huge genomic data files.Many glbase functions can produce graphical outputs,including scatter plots,heatmaps,boxplots and other common analytical displays of high-throughput data such as RNA-seq,ChIP-seq and microarray expression data.glbase is designed to rapidly bring biological data into a Python-based analytical environment to facilitate analysis and data processing.In summary,glbase is a flexible and multifunctional toolkit that allows the combination and analysis of high-throughput data(especially next-generation sequencing and genome-wide data),and which has been instrumental in the analysis of complex data sets.glbase is freely available at http://bitbucket.org/oaxiom/glbase/.展开更多
基金supported by the National Key Technologies R&D Program of China(No.2021YFC2500700)the National Natural Science Foundation of China(No.82003406)+2 种基金the Natural Science Foundation of Hebei Province(H2022209073)the China Postdoctoral Science Foundation(2023M733985)the CAMS Institute of Respiratory Medicine Grant for Young Scholars(2023-ZF-69).
文摘Monocyte-derived macrophages(MoMacs)are the most important effector cells that cause pulmonary fibrosis.However,the characteristics of MoMac differentiation in silicosis and the mechanisms by which MoMacs affect the progression of pulmonary fibrosis remain unclear.Integration of single-cell and spatial transcriptomic analyses revealed that the silicosis niche was occupied by a subset of MoMacs,identified as Spp1hiMacs,which remain in an immature transitional state of differentiation during silicosis.This study investigated the mechanistic foundations of mitochondrial damage induced by the lipoprotein-associated phospholipase A2(Lp-PLA2,encoded by Pla2g7)–acyl-CoA:lysocardiolipin acyltransferase-1(ALCAT1)–cardiolipin(CL)signaling pathway,which interferes with Spp1hiMac differentiation.We demonstrated that in SiO_(2)-induced MoMacs,Lp-PLA2 induces abnormal CL acylation through the activation of ALCAT1,resulting in impaired mitochondrial localization of PINK1 and LC3B and mitochondrial autophagy defects.Simultaneously,lysosomal dysfunction causes the release of the lysosomal protein cathepsin B into the cytoplasm,which involves M1 and M2 macrophage polarization and the activation of proinflammatory and profibrotic pathways.Furthermore,we assessed the efficacy of the Lp-PLA2 inhibitor darapladib in ameliorating silica-induced pulmonary fibrosis in a murine model.Our findings enhance our understanding of silicosis pathogenesis and offer promising opportunities for developing targeted therapies to mitigate fibrotic progression and maintain lung function in affected individuals.
文摘Genomic datasets and the tools to analyze them have proliferated at an astonishing rate.However,such tools are often poorly integrated with each other:each program typically produces its own custom output in a variety of non-standard file formats.Here we present glbase,a framework that uses a flexible set of descriptors that can quickly parse non-binary data files.glbase includes many functions to intersect two lists of data,including operations on genomic interval data and support for the efficient random access to huge genomic data files.Many glbase functions can produce graphical outputs,including scatter plots,heatmaps,boxplots and other common analytical displays of high-throughput data such as RNA-seq,ChIP-seq and microarray expression data.glbase is designed to rapidly bring biological data into a Python-based analytical environment to facilitate analysis and data processing.In summary,glbase is a flexible and multifunctional toolkit that allows the combination and analysis of high-throughput data(especially next-generation sequencing and genome-wide data),and which has been instrumental in the analysis of complex data sets.glbase is freely available at http://bitbucket.org/oaxiom/glbase/.
