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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.

Original publication

DOI

10.1038/s41467-019-13853-4

Type

Journal article

Journal

Nat commun

Publication Date

09/01/2020

Volume

11

Keywords

Animals, CD4-Positive T-Lymphocytes, Cell Differentiation, Cells, Cultured, Female, Granulocyte-Macrophage Colony-Stimulating Factor, Hematopoiesis, Extramedullary, Hematopoietic Stem Cells, Interleukin-33, Mast Cells, Mice, Mice, Inbred BALB C, Myelopoiesis, Spondylarthritis