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

Daniel Regan-Komito, James W. Swann, Philippos Demetriou, E. Suzanne Cohen, Nicole J. Horwood, Stephen N. Sansom and Thibault Griseri ()
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Daniel Regan-Komito: University of Oxford, Roosevelt Drive
James W. Swann: University of Oxford, Roosevelt Drive
Philippos Demetriou: University of Oxford, Roosevelt Drive
E. Suzanne Cohen: Biopharmaceutical Research Division, AstraZeneca
Nicole J. Horwood: University of Oxford, Roosevelt Drive
Stephen N. Sansom: University of Oxford, Roosevelt Drive
Thibault Griseri: University of Oxford, Roosevelt Drive

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-019-13853-4

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