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CITED2 limits pathogenic inflammatory gene programs in myeloid cells

Monocyte‐derived macrophages are the major innate immune cells that provide the first line of cellular defense against infections or injuries. These recruited macrophages at the site of inflammation are exposed to a broad range of cytokines that categorically incite a robust pro‐inflammatory respons...

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Autores principales: Pong Ng, Hang, Kim, Gun‐Dong, Ricky Chan, E., Dunwoodie, Sally L., Mahabeleshwar, Ganapati H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496281/
https://www.ncbi.nlm.nih.gov/pubmed/32697413
http://dx.doi.org/10.1096/fj.202000864R
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author Pong Ng, Hang
Kim, Gun‐Dong
Ricky Chan, E.
Dunwoodie, Sally L.
Mahabeleshwar, Ganapati H.
author_facet Pong Ng, Hang
Kim, Gun‐Dong
Ricky Chan, E.
Dunwoodie, Sally L.
Mahabeleshwar, Ganapati H.
author_sort Pong Ng, Hang
collection PubMed
description Monocyte‐derived macrophages are the major innate immune cells that provide the first line of cellular defense against infections or injuries. These recruited macrophages at the site of inflammation are exposed to a broad range of cytokines that categorically incite a robust pro‐inflammatory response. However, macrophage pro‐inflammatory activation must be under exquisite control to avert unbridled inflammation. Thus, endogenous mechanisms must exist that rigorously preserve macrophage quiescence and yet, allow nimble pro‐inflammatory macrophage response with precise spatiotemporal control. Herein, we identify the CBP/p300‐interacting transactivator with glutamic acid/aspartic acid‐rich carboxyl‐terminal domain 2 (CITED2) as a critical intrinsic negative regulator of inflammation, which broadly attenuates pro‐inflammatory gene programs in macrophages. Our in vivo studies revealed that myeloid‐CITED2 deficiency significantly heightened macrophages and neutrophils recruitment to the site of inflammation. Our integrated transcriptomics and gene set enrichment analysis (GSEA) studies uncovered that CITED2 deficiency broadly enhances NFκB targets, IFNγ/IFNα responses, and inflammatory response gene expression in macrophages. Using complementary gain‐ and loss‐of‐function studies, we observed that CITED2 overexpression attenuate and CITED2 deficiency elevate LPS‐induced NFκB transcriptional activity and NFκB‐p65 recruitment to target gene promoter in macrophages. More importantly, blockade of NFκB signaling completely reversed elevated pro‐inflammatory gene expression in macrophages. Collectively, our findings show that CITED2 restrains NFκB activation and curtails broad pro‐inflammatory gene programs in myeloid cells.
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spelling pubmed-74962812020-09-25 CITED2 limits pathogenic inflammatory gene programs in myeloid cells Pong Ng, Hang Kim, Gun‐Dong Ricky Chan, E. Dunwoodie, Sally L. Mahabeleshwar, Ganapati H. FASEB J Research Articles Monocyte‐derived macrophages are the major innate immune cells that provide the first line of cellular defense against infections or injuries. These recruited macrophages at the site of inflammation are exposed to a broad range of cytokines that categorically incite a robust pro‐inflammatory response. However, macrophage pro‐inflammatory activation must be under exquisite control to avert unbridled inflammation. Thus, endogenous mechanisms must exist that rigorously preserve macrophage quiescence and yet, allow nimble pro‐inflammatory macrophage response with precise spatiotemporal control. Herein, we identify the CBP/p300‐interacting transactivator with glutamic acid/aspartic acid‐rich carboxyl‐terminal domain 2 (CITED2) as a critical intrinsic negative regulator of inflammation, which broadly attenuates pro‐inflammatory gene programs in macrophages. Our in vivo studies revealed that myeloid‐CITED2 deficiency significantly heightened macrophages and neutrophils recruitment to the site of inflammation. Our integrated transcriptomics and gene set enrichment analysis (GSEA) studies uncovered that CITED2 deficiency broadly enhances NFκB targets, IFNγ/IFNα responses, and inflammatory response gene expression in macrophages. Using complementary gain‐ and loss‐of‐function studies, we observed that CITED2 overexpression attenuate and CITED2 deficiency elevate LPS‐induced NFκB transcriptional activity and NFκB‐p65 recruitment to target gene promoter in macrophages. More importantly, blockade of NFκB signaling completely reversed elevated pro‐inflammatory gene expression in macrophages. Collectively, our findings show that CITED2 restrains NFκB activation and curtails broad pro‐inflammatory gene programs in myeloid cells. John Wiley and Sons Inc. 2020-07-22 2020-09 /pmc/articles/PMC7496281/ /pubmed/32697413 http://dx.doi.org/10.1096/fj.202000864R Text en © 2020 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Research Articles
Pong Ng, Hang
Kim, Gun‐Dong
Ricky Chan, E.
Dunwoodie, Sally L.
Mahabeleshwar, Ganapati H.
CITED2 limits pathogenic inflammatory gene programs in myeloid cells
title CITED2 limits pathogenic inflammatory gene programs in myeloid cells
title_full CITED2 limits pathogenic inflammatory gene programs in myeloid cells
title_fullStr CITED2 limits pathogenic inflammatory gene programs in myeloid cells
title_full_unstemmed CITED2 limits pathogenic inflammatory gene programs in myeloid cells
title_short CITED2 limits pathogenic inflammatory gene programs in myeloid cells
title_sort cited2 limits pathogenic inflammatory gene programs in myeloid cells
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496281/
https://www.ncbi.nlm.nih.gov/pubmed/32697413
http://dx.doi.org/10.1096/fj.202000864R
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