GM-CSF drives dysregulated hematopoietic stem cell activity and pathogenic extramedullary myelopoiesis in experimental spondyloarthritis

Regan-Komito, Daniel, Swann, James W., Demetriou, Philippos, Cohen, E. Suzanne, Horwood, Nicole J., Sansom, Stephen N. and Griseri, Thibault (2020) GM-CSF drives dysregulated hematopoietic stem cell activity and pathogenic extramedullary myelopoiesis in experimental spondyloarthritis. Nature Communications, 11 (1). ISSN 2041-1723

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Abstract

Dysregulated hematopoiesis occurs in several chronic inflammatory diseases, but it remains unclear how hematopoietic stem cells (HSCs) in the bone marrow (BM) sense peripheral inflammation and contribute to tissue damage in arthritis. Here, we show the HSC gene expression program is biased toward myelopoiesis and differentiation skewed toward granulocyte-monocyte progenitors (GMP) during joint and intestinal inflammation in experimental spondyloarthritis (SpA). GM-CSF-receptor is increased on HSCs and multipotent progenitors, favoring a striking increase in myelopoiesis at the earliest hematopoietic stages. GMP accumulate in the BM in SpA and, unexpectedly, at extramedullary sites: in the inflamed joints and spleen. Furthermore, we show that GM-CSF promotes extramedullary myelopoiesis, tissue-toxic neutrophil accumulation in target organs, and GM-CSF prophylactic or therapeutic blockade substantially decreases SpA severity. Surprisingly, besides CD4+ T cells and innate lymphoid cells, mast cells are a source of GM-CSF in this model, and its pathogenic production is promoted by the alarmin IL-33.

Item Type: Article
Uncontrolled Keywords: chemistry(all),biochemistry, genetics and molecular biology(all),physics and astronomy(all) ,/dk/atira/pure/subjectarea/asjc/1600
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
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Depositing User: LivePure Connector
Date Deposited: 25 Jan 2020 03:33
Last Modified: 05 Apr 2020 00:50
URI: https://ueaeprints.uea.ac.uk/id/eprint/73778
DOI: 10.1038/s41467-019-13853-4

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