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Comparison of two human organoid models of lung and intestinal inflammation reveals Toll-like receptor signalling activation and monocyte recruitment.

ABSTRACT: Comparison of two human organoid models of lung and intestinal inflammation reveals Toll-like receptor signalling activation and monocyte recruitment.

PROVIDER: PRJNA637292 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11924300.fastq.gz	Fastqsanger.gz
	SRR11924301.fastq.gz	Fastqsanger.gz
	SRR11924278.fastq.gz	Fastqsanger.gz
	SRR11924279.fastq.gz	Fastqsanger.gz
	SRR11924280.fastq.gz	Fastqsanger.gz

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Comparison of two human organoid models of lung and intestinal inflammation reveals Toll-like receptor signalling activation and monocyte recruitment.

Project description:OBJECTIVES: The activation of immune responses in mucosal tissues is a key factor for the development and sustainment of several pathologies including infectious diseases and autoimmune diseases. However, translational research and personalized medicine struggle to advance because of the lack of suitable preclinical models that successfully mimic the complexity of human tissues without relying on in vivo mouse models. Here we propose two in vitro human 3D tissue models, deprived of any resident leukocytes, to model mucosal tissue inflammatory processes. METHODS: We developed human 3D lung and intestinal organoids differentiated from induced pluripotent stem cells to model mucosal tissues. We then compared their response to a panel of microbial ligands and investigated their ability to attract and host human primary monocytes. RESULTS: Mature lung and intestinal organoids incorporated epithelial (EpCAM+) and mesenchymal (CD73+) cells which responded to toll-like receptor stimulation by releasing pro-inflammatory cytokines and expressing tissue inflammatory markers including MMP9, COX2 and CRP. When added to the organoid culture, primary human monocytes migrated towards the organoids and began to differentiate to an “intermediate-like” phenotype characterised by increased levels of CD14 and CD16. CONCLUSION: We show that human mucosal organoids exhibit proper immune functions and successfully mimic an immunocompetent tissue micro-environment able to host patient-derived immune cells. Our experimental setup provides a novel tool to tackle the complexity of immune responses in mucosal tissues which can be tailored to different human pathologies.

2020-06-05 | GSE151796 | GEO

Comparison of two human organoid models of lung and intestinal inflammation reveals Toll-like receptor signalling activation and monocyte recruitment.

Project description:Objectives:The activation of immune responses in mucosal tissues is a key factor for the development and sustainment of several pathologies including infectious diseases and autoimmune diseases. However, translational research and personalised medicine struggle to advance because of the lack of suitable preclinical models that successfully mimic the complexity of human tissues without relying on in vivo mouse models. Here, we propose two in vitro human 3D tissue models, deprived of any resident leucocytes, to model mucosal tissue inflammatory processes. Methods:We developed human 3D lung and intestinal organoids differentiated from induced pluripotent stem cells to model mucosal tissues. We then compared their response to a panel of microbial ligands and investigated their ability to attract and host human primary monocytes. Results:Mature lung and intestinal organoids comprised epithelial (EpCAM+) and mesenchymal (CD73+) cells which responded to Toll-like receptor stimulation by releasing pro-inflammatory cytokines and expressing tissue inflammatory markers including MMP9, COX2 and CRP. When added to the organoid culture, primary human monocytes migrated towards the organoids and began to differentiate to an 'intermediate-like' phenotype characterised by increased levels of CD14 and CD16. Conclusion:We show that human mucosal organoids exhibit proper immune functions and successfully mimic an immunocompetent tissue microenvironment able to host patient-derived immune cells. Our experimental set-up provides a novel tool to tackle the complexity of immune responses in mucosal tissues which can be tailored to different human pathologies.

| S-EPMC7200218 | biostudies-literature

Deciphering the resiquimod induced toll-like receptor signalling pathway in chickens

Project description:Deciphering the resiquimod induced toll-like receptor signalling pathway in chickens

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Rapid Monocyte Recruitment Dictates the Therapeutic Efficacy of Focal Radiotherapy

Project description:The recruitment of monocytes and their differentiation into immunosuppressive cells is associated with the negative outcome of non-conformal radiotherapy (RT). However, non-conformal RT is irrelevant in the clinic, and little is known about the role of monocytes following radiotherapy modes used in patients, such as conformal radiotherapy (CRT). Here, we investigated the acute immune infiltration post-CRT. Contrary to non-conformal RT approaches, we found that CRT induces a rapid and robust recruitment of monocytes to the tumor that minimally differentiate into tumor-associated macrophages (TAM) or dendritic cells (DC), but instead upregulate major histocompatibility complex II (MHCII) and costimulatory molecules. We establish that these large numbers of infiltrating monocytes are responsible for increasing type I interferon in the tumor microenvironment (TME), activation of CD8+ T cells and the reduction in tumor burden. Importantly, we demonstrate that rapid monocyte infiltration to the TME is hindered when RT inadvertently affects healthy tissues. Our results unravel a positive role of monocytes during clinically relevant modes of RT and demonstrate that limiting exposure of healthy tissues to radiation has a positive therapeutic effect on the overall immune response within the tumor.

2022-06-30 | MSV000089775 | MassIVE

Resetting proteostasis in aged animals with ISRIB prevents recruitment of profibrotic monocyte-derived alveolar macrophages during pulmonary fibrosis

Project description:Aging is among the most important risk factors for the development of pulmonary fibrosis. Inappropriate or prolonged activation of the integrated stress response has been implicated in the pathobiology of both aging and pulmonary fibrosis. We found that a small molecule that relieves translational inhibition induced by activation of the integrated stress response (ISRIB) attenuated the severity pulmonary fibrosis in young and old mice. We demonstrate that severe fibrosis in old mice was associated with increased number of pathogenic monocyte-derived alveolar macrophages. Using transcriptomic profiling we found that ISRIB modulates stress response signaling in alveolar epithelial cells resulting in decreased recruitment of pathogenic monocyte-derived alveolar macrophages. Thus our data suggest that inhibition of the integrated stress response in the lung epithelium can ameliorate pulmonary fibrosis by preventing the recruitment of monocyte-derived alveolar macrophages.

2021-04-16 | GSE145295 | GEO

Resetting proteostasis in aged animals with ISRIB prevents recruitment of profibrotic monocyte-derived alveolar macrophages during pulmonary fibrosis [AT2]

2021-04-16 | GSE145771 | GEO

LPS induced CXCL10 chemokine production via IFN- α receptor and toll-like receptor 4 signalling

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Resetting proteostasis in aged animals with ISRIB prevents recruitment of profibrotic monocyte-derived alveolar macrophages during pulmonary fibrosis [dataset 2]

2021-04-16 | GSE145590 | GEO

Bacterial infection disrupts established germinal center reactions through monocyte recruitment and impaired metabolic adaptation [Bulk RNA-seq]

Project description:Consecutive exposures to different pathogens are very common and often alter host immune responses. Yet, it remains unknown how a secondary bacterial infection interferes with an ongoing adaptive immune response elicited against primary invading pathogens. Here, we demonstrate that pre-existing germinal center (GC) B cells are incapable of enduring radical metabolic changes induced by recruited Sca-1+ monocytes during Salmonella Typhimurium (STm) infection. GCs-induced by influenza, plasmodium and commensals deteriorated upon STm infection. GC collapse was independent of direct bacterial interactions with B cells, but rather, was induced through recruitment of CCR2-dependent Sca-1+ monocytes. GC collapse was dependent on non-B cell TLR-4, TNFα and IFNγ, which was essential for Sca-1+ monocyte differentiation in the bone-marrow. Monocyte recruitment and GC disruption also occurred during LPS-supplemented vaccination and Listeria monocytogenes infection. Thus, systemic activation of the innate immune response upon lethal bacterial infection is induced at the expense of antibody-mediated immunity.

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Bacterial infection disrupts established germinal center reactions through monocyte recruitment and impaired metabolic adaptation [Single-cell RNA-seq]

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