Lamina Propria Phagocyte Profiling Reveals Targetable Signaling Pathways in Refractory Inflammatory Bowel Disease
Lamina propria phagocytes are key mediators of inflammatory bowel disease (IBD). We aimed to understand the transcriptomic and functional differences in these cells based on location, disease type, inflammation state, and medication use in patients with IBD. Phagocytic immune cells in the lamina pro...
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Published in | Gastro hep advances Vol. 1; no. 3; pp. 380 - 392 |
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Main Authors | , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Elsevier Inc
2022
Elsevier |
Subjects | |
Online Access | Get full text |
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Summary: | Lamina propria phagocytes are key mediators of inflammatory bowel disease (IBD). We aimed to understand the transcriptomic and functional differences in these cells based on location, disease type, inflammation state, and medication use in patients with IBD.
Phagocytic immune cells in the lamina propria, as defined by the marker CD11b, were isolated from 54 unique patients (n = 111 gut mucosal biopsies). We performed flow cytometry for cell phenotyping (n = 30) and RNA sequencing with differential gene expression analysis (n = 58). We further cultured these cells in vitro and exposed them to janus kinase inhibitors to measure cytokine output (n = 27). Finally, we matched patient genomic data to our RNA sequencing data to perform candidate gene expression quantitative trait locus analysis (n = 34).
We found distinct differences in gene expression between CD11b+ cells from the colon vs ileum, as well as in different inflammatory states and, to a lesser degree, IBD types (Crohn’s disease or ulcerative colitis). These genes mapped to targetable immune pathways and metabolic and cancer pathways. We further explored the janus kinase-signal transducer and activator of transcription pathway, which was upregulated across many comparisons including in biopsies from anti–tumor necrosis factor refractory patients. We found that isolated CD11b+ cells treated with janus kinase inhibitors had decreased secretion of cytokines tumor necrosis factorα and interleukin-8 (P ≤ .05). We also found 3 genetic variants acting as expression quantitative trait loci (P ≤ .1) within our CD11b+ data set.
Lamina propria phagocytes from IBD mucosa provide pathogenetic clues on the nature of treatment refractoriness and inform new targets for therapy. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Authors’ Contributions Gillian E. Jacobsen contributed to study concept and design, acquisition of data, analysis and interpretation of data, drafting of the manuscript, and statistical analysis; Irina Fernández contributed to study concept and design, acquisition of data, drafting of the manuscript, and administrative and material support; Maria A. Quintero contributed to acquisition of data, drafting of the manuscript, and material support; Ana M. Santander contributed to acquisition of data, drafting of the manuscript, statistical analysis, and material support; Judith Pignac-Kobinger contributed to study concept and design, drafting of the manuscript, and administrative support and obtained funding; Oriana M. Damas contributed to acquisition of data; Amar R. Deshpande contributed to acquisition of data; David H. Kerman contributed to acquisition of data; Yuguang Ban contributed to statistical analysis and critical revision of the manuscript for important intellectual content; Zhen Gao contributed to statistical analysis and technical support; Tiago C. Silva contributed to statistical analysis and critical revision of the manuscript for important intellectual content; Lily Wang contributed to statistical analysis and critical revision of the manuscript for important intellectual content; Ashley H. Beecham contributed to acquisition of data, statistical analysis, drafting of the manuscript, and critical revision of the manuscript for important intellectual content; Jacob L. McCauley contributed to analysis and interpretation of data and critical revision of the manuscript for important intellectual content; Juan F. Burgueño contributed to study concept and design, analysis and interpretation of data, drafting of the manuscript, and critical revision of the manuscript for important intellectual content and obtained funding; Maria T. Abreu contributed to study concept and design, acquisition of data, analysis and interpretation of data, drafting of the manuscript, critical revision of the manuscript for important intellectual content, and study supervision and obtained funding. |
ISSN: | 2772-5723 2772-5723 |
DOI: | 10.1016/j.gastha.2022.01.005 |