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Targeting of cannabinoid receptor 1 for antagonism in profibrotic alveolar macrophages mitigates pulmonary fibrosis

ABSTRACT: Targeting of cannabinoid receptor 1 for antagonism in profibrotic alveolar macrophages mitigates pulmonary fibrosis

PROVIDER: PRJNA1140217 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR29998849_1.fastq.gz	Fastqsanger.gz
	SRR29998849_2.fastq.gz	Fastqsanger.gz
	SRR29998850_1.fastq.gz	Fastqsanger.gz
	SRR29998850_2.fastq.gz	Fastqsanger.gz
	SRR29998851_1.fastq.gz	Fastqsanger.gz

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Targeting of cannabinoid receptor 1 for antagonism in profibrotic alveolar macrophages mitigates pulmonary fibrosis

Project description:Pulmonary fibrosis (PF) is a life-threatening disease that requires effective and well-tolerated therapeutic modalities. Previously, the distinct pathogenic roles of cannabinoid receptor 1 (CB1R) and inducible nitric oxide synthase (iNOS) in the lungs and their joint therapeutic targeting were highlighted in PF. However, the cell-specific role of CB1R in PF has not been explored. Here, we demonstrate that CB1R in alveolar macrophages (AMs) mediates the release of anandamide into the alveoli, which promotes PF by inducing profibrotic macrophages that are accessible to locally delivered antifibrotic therapy. A multitargeted therapy may improve therapeutic efficacy in PF. Pulmonary delivery of 0.5 mg/kg/day MRI-1867 (zevaquenabant), a peripherally acting hybrid CB1R/iNOS inhibitor, is as effective as systemic delivery of 10 mg/kg/day, and also matches the efficacy of nintedanib in mitigating bleomycin-induced PF. A systems pharmacology approach reveals that zevaquenabant and nintedanib treatments reverse pathologic changes in both distinct and shared PF-related pathways, which are conserved in human and mouse. Moreover, zevaquenabant treatment also attenuated fibrosis and profibrotic mediators in human precision-cut lung slices. These findings establish CB1R-expressing AMs as a therapeutic target and support local delivery of dual CB1R/iNOS inhibitor zevaquenabant by inhalation as an effective, well-tolerated, and safer strategy for PF.

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Profibrotic monocyte-derived alveolar macrophages as a biomarker and therapeutic target in systemic sclerosis-associated interstitial lung disease

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GATA2 deficiency drives a profibrotic program and metabolic dysfunction in alveolar macrophages

Project description:GATA2 deficiency drives a profibrotic program and metabolic dysfunction in alveolar macrophages

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Integrin beta-1 (Itgb1) in profibrotic myofibroblasts

Project description:Fibrosis due to extracellular matrix (ECM) secretion from myofibroblasts complicates many chronic liver diseases causing scarring and organ failure. Integrin-dependent interaction with scar ECM promotes profibrotic features. This microarray study was performed to clarify the role of integrin beta-1 (Itgb1) in profibrotic myofibroblasts.

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Expansion of profibrotic monocyte-derived alveolar macrophages in patients with persistent respiratory symptoms and radiographic abnormalities after COVID-19 [PASC]

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Expansion of profibrotic monocyte-derived alveolar macrophages in patients with persistent respiratory symptoms and radiographic abnormalities after COVID-19 [NEP]

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Expansion of profibrotic monocyte-derived alveolar macrophages in patients with persistent respiratory symptoms and radiographic abnormalities after COVID-19 [BAL]

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Project description:Little is known about the relative importance of monocyte and tissue-resident macrophages in the development of lung fibrosis. We show that specific genetic deletion of monocyte-derived alveolar macrophages after their recruitment to the lung ameliorated lung fibrosis, whereas tissue-resident alveolar macrophages did not contribute to fibrosis. Using transcriptomic profiling of flow-sorted cells, we found that monocyte to alveolar macrophage differentiation unfolds continuously over the course of fibrosis and its resolution. During the fibrotic phase, monocyte-derived alveolar macrophages differ significantly from tissue-resident alveolar macrophages in their expression of profibrotic genes. A population of monocyte-derived alveolar macrophages persisted in the lung for one year after the resolution of fibrosis, where they became increasingly similar to tissue-resident alveolar macrophages. Human homologues of profibrotic genes expressed by mouse monocyte-derived alveolar macrophages during fibrosis were up-regulated in human alveolar macrophages from fibrotic compared with normal lungs. Our findings suggest that selectively targeting alveolar macrophage differentiation within the lung may ameliorate fibrosis without the adverse consequences associated with global monocyte or tissue-resident alveolar macrophage depletion.

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GATA2 deficiency drives a profibrotic program and metabolic dysfunction in alveolar macrophages

Project description:Alveolar macrophages (AMs) have homeostatic, anti-inflammatory programming to limit tissue damage in response to minor challenge and the distinct, lung-specific function of catabolizing lipid-rich pulmonary surfactant to support gas exchange. GATA transcription factors (TFs) have been well established to cooperate with and antagonize other TFs to shape immune cell fates and GATA2 is expressed in a lung-specific manner in macrophages. Both mutations and lung macrophage downregulation of GATA2 have been associated with chronic pulmonary pathologies in humans, but the role of GATA2 in shaping AM function is not well defined. Using mice with myeloid-specific deletion of the GATA2 DNA binding C-terminal zinc finger domain, we show that GATA2 deficiency promotes a profibrotic state and metabolic dysfunction in AMs in response to type 2 stimuli. While homeostatic functions of AMs remained largely intact, GATA2 deficiency increased expression of genes associated with pulmonary fibrosis in response to IL-33-induced inflammation. Coincident with GATA2-dependent expression of genes in metabolic pathways, seahorse metabolic flux analysis suggests that AM metabolism is compromised, likely due to mitochondrial dysregulation, in the absence of GATA2. AM GATA2-dependent gene networks are enriched for targets of TFs previously demonstrated to interact with GATA2 in other cellular contexts, including PU.1, PPARγ, and other TFs that regulate AM homeostatic and inflammatory function. Thus, GATA2 mediates AM metabolic and transcriptomic programming to limit responses that support the development pulmonary fibrosis.

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