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Lamina Propria Phagocyte Profiling Reveals Targetable Signaling Pathways in Refractory Inflammatory Bowel Disease

BACKGROUND AND AIMS: 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. METHODS: Phagocytic...

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Autores principales: Jacobsen, Gillian E., Fernández, Irina, Quintero, Maria A., Santander, Ana M., Pignac-Kobinger, Judith, Damas, Oriana M., Deshpande, Amar R., Kerman, David H., Ban, Yuguang, Gao, Zhen, Silva, Tiago C., Wang, Lily, Beecham, Ashley H., McCauley, Jacob L., Burgueño, Juan F., Abreu, Maria T.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9438737/
https://www.ncbi.nlm.nih.gov/pubmed/36061955
http://dx.doi.org/10.1016/j.gastha.2022.01.005
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author Jacobsen, Gillian E.
Fernández, Irina
Quintero, Maria A.
Santander, Ana M.
Pignac-Kobinger, Judith
Damas, Oriana M.
Deshpande, Amar R.
Kerman, David H.
Ban, Yuguang
Gao, Zhen
Silva, Tiago C.
Wang, Lily
Beecham, Ashley H.
McCauley, Jacob L.
Burgueño, Juan F.
Abreu, Maria T.
author_facet Jacobsen, Gillian E.
Fernández, Irina
Quintero, Maria A.
Santander, Ana M.
Pignac-Kobinger, Judith
Damas, Oriana M.
Deshpande, Amar R.
Kerman, David H.
Ban, Yuguang
Gao, Zhen
Silva, Tiago C.
Wang, Lily
Beecham, Ashley H.
McCauley, Jacob L.
Burgueño, Juan F.
Abreu, Maria T.
author_sort Jacobsen, Gillian E.
collection PubMed
description BACKGROUND AND AIMS: 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. METHODS: 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). RESULTS: 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 factora and interleukin-8 (P ≤ .05). We also found 3 genetic variants acting as expression quantitative trait loci (P ≤ .1) within our CD11b(+) data set. CONCLUSIONS: 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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spelling pubmed-94387372022-09-02 Lamina Propria Phagocyte Profiling Reveals Targetable Signaling Pathways in Refractory Inflammatory Bowel Disease Jacobsen, Gillian E. Fernández, Irina Quintero, Maria A. Santander, Ana M. Pignac-Kobinger, Judith Damas, Oriana M. Deshpande, Amar R. Kerman, David H. Ban, Yuguang Gao, Zhen Silva, Tiago C. Wang, Lily Beecham, Ashley H. McCauley, Jacob L. Burgueño, Juan F. Abreu, Maria T. Gastro Hep Adv Article BACKGROUND AND AIMS: 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. METHODS: 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). RESULTS: 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 factora and interleukin-8 (P ≤ .05). We also found 3 genetic variants acting as expression quantitative trait loci (P ≤ .1) within our CD11b(+) data set. CONCLUSIONS: Lamina propria phagocytes from IBD mucosa provide pathogenetic clues on the nature of treatment refractoriness and inform new targets for therapy. 2022 2022-03-30 /pmc/articles/PMC9438737/ /pubmed/36061955 http://dx.doi.org/10.1016/j.gastha.2022.01.005 Text en https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by/4.0/) ).
spellingShingle Article
Jacobsen, Gillian E.
Fernández, Irina
Quintero, Maria A.
Santander, Ana M.
Pignac-Kobinger, Judith
Damas, Oriana M.
Deshpande, Amar R.
Kerman, David H.
Ban, Yuguang
Gao, Zhen
Silva, Tiago C.
Wang, Lily
Beecham, Ashley H.
McCauley, Jacob L.
Burgueño, Juan F.
Abreu, Maria T.
Lamina Propria Phagocyte Profiling Reveals Targetable Signaling Pathways in Refractory Inflammatory Bowel Disease
title Lamina Propria Phagocyte Profiling Reveals Targetable Signaling Pathways in Refractory Inflammatory Bowel Disease
title_full Lamina Propria Phagocyte Profiling Reveals Targetable Signaling Pathways in Refractory Inflammatory Bowel Disease
title_fullStr Lamina Propria Phagocyte Profiling Reveals Targetable Signaling Pathways in Refractory Inflammatory Bowel Disease
title_full_unstemmed Lamina Propria Phagocyte Profiling Reveals Targetable Signaling Pathways in Refractory Inflammatory Bowel Disease
title_short Lamina Propria Phagocyte Profiling Reveals Targetable Signaling Pathways in Refractory Inflammatory Bowel Disease
title_sort lamina propria phagocyte profiling reveals targetable signaling pathways in refractory inflammatory bowel disease
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9438737/
https://www.ncbi.nlm.nih.gov/pubmed/36061955
http://dx.doi.org/10.1016/j.gastha.2022.01.005
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