Tissue adaptaion of intestinal eosinophils in mice
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ABSTRACT:
PROVIDER: PRJNA767596 | ENA |
REPOSITORIES: ENA
Dataset's files
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| SRR16129032.fastq.gz | Fastqsanger.gz | |||
| SRR16129033.fastq.gz | Fastqsanger.gz | |||
| SRR16129034.fastq.gz | Fastqsanger.gz | |||
| SRR16129035.fastq.gz | Fastqsanger.gz | |||
| SRR16129036.fastq.gz | Fastqsanger.gz |
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Project description:The aryl hydrocarbon receptor partially controls tissue adaptaion of intestinal eosinophils in mice
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Project description:Intestinal homeostasis following postnatal microbial colonization requires the coordination of multiple processes, including the activation of immune cells, cell-cell communication, the controlled deposition of extracellular matrix, and epithelial cell turnover and differentiation. The intestine harbors the largest frequency of resident eosinophils of all homeostatic organs, yet the functional significance of eosinophil residence in the gut remains unclear. Eosinophils are equipped to both respond to, and modify, their local tissue environment and thus are able to regulate the adaption of tissues to environmental changes. We report a critical role for eosinophils in regulating villous structure, barrier integrity and motility in the small intestine. Notably, the microbiota was identified as a key driver of small intestinal eosinophil activation and function. Collectively our findings demonstrate a critical role for eosinophils in facilitating mutualistic interactions between host and microbiota and provide a rationale for the functional significance of their early life recruitment in the small intestine.
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Project description:In the past decade, single-cell transcriptomics has helped uncover new cell types and states and led to the construction of a cellular compendium of health and disease1. Still, some difficult-to-sequence cell types remain absent from cell atlases. Eosinophils, elusive granulocytes implicated in a plethora of human pathologies2,3, are among these uncharted cell types. To date, the heterogeneity of eosinophils and the gene programs underpinning their pleiotropic functions remain poorly understood4. In the present study, we provide the first comprehensive single-cell transcriptomic profiling of murine eosinophils. We identify an active and a basal population of intestinal eosinophils, differing in their transcriptome, surface proteome and spatial localization. By means of genome wide CRISPR inhibition screen and functional assays, we dissect a mechanism by which IL-33 and IFN-? induce active eosinophil accumulation in the inflamed colon. Active eosinophils are endowed with bactericidal and T cell regulatory activity, and express the co-stimulatory molecules CD80 and PD-L1. Notably, active eosinophils are enriched in the lamina propria of a small cohort of inflammatory bowel disease patients and tightly associate with CD4+ T cells. Our findings provide novel insights into the biology of this elusive cell type and highlight its crucial contribution to intestinal homeostasis, immune regulation and host defence. Furthermore, we lay a framework for the characterization of eosinophils in human gastrointestinal diseases.
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Project description:No longer regarded as simply end-stage cytotoxic effectors, eosinophils are now recognized as complex cells with unique phenotypes that develop in response to the local microenvironment. In our previous study, we documented eosinophil infiltration in association with characteristic muscle damage in the dystrophin-deficient (mdx) mouse model of Duchenne muscular dystrophy. In this earlier study, we found that eosinophils did not promote formation of muscle lesions, as these persisted in eosinophil-deficient mdx.PHIL mice. To obtain additional insight into these findings, we performed RNA sequencing on eosinophils isolated from muscle tissue of mdx, IL5tg, and mdx.IL5tg mouse strains. We discovered profound up-regulation of classical eosinophil effector proteins (major basic protein-1, eosinophil peroxidase, and eosinophil-associated ribonucleases, or RNases) in eosinophils isolated from lesion-free muscle from IL5tg mice. By contrast, we observed significant upregulation of tissue remodeling genes, including proteases, extracellular matrix components, collagen, and skeletal muscle precursors, as well as the immunomodulatory receptor, TREM2, in eosinophils isolated from skeletal muscle tissue from the dystrophin-deficient mdx mouse strain. The anti-inflammatory properties of TREM2 have been described in the monocyte/macrophage lineage; however, there are no previous studies documenting TREM2 expression in eosinophils. Here we show that TREM2 is critical for full growth and differentiation of bone marrow-derived eosinophil cultures and for full expression of toll-like receptor 4. Immunoreactive TREM2 was also detected on human eosinophils at levels that correlated with donor body mass index. Taken together, our findings provide important insight into the immunomodulatory and remodeling capacity of mouse eosinophils and the flexibility of their gene expression profiles in vivo.
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