Chronic activation of endothelial MAPK disrupts hematopoiesis via NFKB dependent inflammatory stress reversible by SCGF

Pradeep Ramalingam, Michael G. Poulos, Elisa Lazzari, Michael C. Gutkin, David Lopez, Christopher C. Kloss, Michael J. Crowley, Lizabeth Katsnelson, Ana G. Freire, Matthew B. Greenblatt, Christopher Y. Park and Jason M. Butler ()
Additional contact information
Pradeep Ramalingam: Weill Cornell Medical College
Michael G. Poulos: Hackensack University Medical Center
Elisa Lazzari: Hackensack University Medical Center
Michael C. Gutkin: Hackensack University Medical Center
David Lopez: Weill Cornell Medical College
Christopher C. Kloss: Weill Cornell Medical College
Michael J. Crowley: Weill Cornell Medical College
Lizabeth Katsnelson: Weill Cornell Medical College
Ana G. Freire: Hackensack University Medical Center
Matthew B. Greenblatt: Weill Cornell Medical College
Christopher Y. Park: New York University Langone Health, School of Medicine
Jason M. Butler: Hackensack University Medical Center

Nature Communications, 2020, vol. 11, issue 1, 1-20

Abstract: Abstract Inflammatory signals arising from the microenvironment have emerged as critical regulators of hematopoietic stem cell (HSC) function during diverse processes including embryonic development, infectious diseases, and myelosuppressive injuries caused by irradiation and chemotherapy. However, the contributions of cellular subsets within the microenvironment that elicit niche-driven inflammation remain poorly understood. Here, we identify endothelial cells as a crucial component in driving bone marrow (BM) inflammation and HSC dysfunction observed following myelosuppression. We demonstrate that sustained activation of endothelial MAPK causes NF-κB-dependent inflammatory stress response within the BM, leading to significant HSC dysfunction including loss of engraftment ability and a myeloid-biased output. These phenotypes are resolved upon inhibition of endothelial NF-κB signaling. We identify SCGF as a niche-derived factor that suppresses BM inflammation and enhances hematopoietic recovery following myelosuppression. Our findings demonstrate that chronic endothelial inflammation adversely impacts niche activity and HSC function which is reversible upon suppression of inflammation.

Date: 2020
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-020-14478-8 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-14478-8

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-020-14478-8

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().