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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.
Highlights
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
granulocyte-macrophage colony stimulating factor (GM-CSF) treatment recapitulated the myeloid-skewed output from hematopoietic stem and progenitor cell (HSPC) observed with SpA, with a BM increase in granulocyte-monocyte progenitors (GMP) and neutrophils but decrease in megakaryocyte-erythroid progenitors (MEP) and mature erythroid cells and B cells (Supplementary Fig. 2g). These results revealed that the gene expression program of HSCs and multipotent progenitor (MPP) is biased toward myeloid cell differentiation during SpA and that HSPCs are responsive to the pro-myelopoietic effect of GM-CSF as early as at the HSC and MPP stages, before the emergence of GMPs and mature myeloid cells
Source data are provided as Source Data file. State, it was increased ~fourfold in SpA (Fig. 4a). We found that this increase in GMPs was mirrored by significantly higher numbers of colony forming unit-granulocyte macrophage (CFU-GM) derived from splenocytes of arthritic compared to healthy SKG mice (Fig. 4a), and a marked enrichment in splenic neutrophils (Fig. 4b)
Summary
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. SpA encompasses several inflammatory arthropathies, including ankylosing spondylitis (AS), psoriatic arthritis, and enteropathic arthritis, which share common genetic and environmental triggers and pathophysiological mechanisms[10] These include, for example, involvement of the IL-23/Th17 pathway and intestinal dysbiosis[11]. Neutrophils accumulate in the synovial fluid of SpA patients and inflamed entheses (i.e., tendon and ligament insertions into the bone) These overactivated neutrophils are tissue-toxic owing to release of proteases, reactive oxygen species, and inflammatory cytokines that contribute to chronic bone and cartilage damage[13,14]. Neutrophils are short-lived cells and their peripheral numbers are highly dependent on the output from HSPCs in the BM15
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