Abstract
An important comorbidity of chronic inflammation is anemia, which may be related to dysregulated activity of hematopoietic stem and progenitor cells (HSPCs) in the bone marrow (BM). Among HSPCs, we found that the receptor for IL-33, ST2, is expressed preferentially and highly on erythroid progenitors. Induction of inflammatory spondyloarthritis in mice increased IL-33 in BM plasma, and IL-33 was required for inflammation-dependent suppression of erythropoiesis in BM. Conversely, administration of IL-33 in healthy mice suppressed erythropoiesis, decreased hemoglobin expression, and caused anemia. Using purified erythroid progenitors in vitro, we show that IL-33 directly inhibited terminal maturation. This effect was dependent on NF-κB activation and associated with altered signaling events downstream of the erythropoietin receptor. Accordingly, IL-33 also suppressed erythropoietin-accelerated erythropoiesis in vivo. These results reveal a role for IL-33 in pathogenesis of anemia during inflammatory disease and define a new target for its treatment.
Highlights
Chronic inflammatory diseases cause local effects in diseased organs, but owing to the systemic effects of inflammation they are frequently associated with important comorbidities in other locations, including the blood and bone marrow (BM; Argollo et al, 2019; Turesson, 2016)
This principle is exemplified by patients with rheumatoid arthritis and spondyloarthritis (SpA), a complex of diseases causing chronic inflammation of the axial spine, peripheral joints, and small intestine (Ranganathan et al, 2017), who may develop anemia of inflammatory disease (AID) or BM dysfunction (Furst et al, 2013; Smith et al, 1992)
We demonstrate that IL-33 exerts a direct effect on erythroid progenitors in vitro to inhibit differentiation into mature RBCs, contingent on activation of NF-κB, and inhibits EPO-induced signaling pathways downstream of the EPO receptor (EPO-R) in a mechanism unrelated to those of previously described suppressors of erythropoiesis
Summary
Chronic inflammatory diseases cause local effects in diseased organs, but owing to the systemic effects of inflammation they are frequently associated with important comorbidities in other locations, including the blood and bone marrow (BM; Argollo et al, 2019; Turesson, 2016). But important contributors include reduced absorption of iron, decreased secretion of or responsiveness to erythropoietin (EPO), and suppressive effects of inflammatory cytokines on erythroid progenitors in BM (Nemeth and Ganz, 2014; Weiss and Goodnough, 2005). Contrary to their traditional image as isolated cells in secluded niches, hematopoietic stem and progenitor cells (HSPCs), including erythroid progenitors, express receptors for inflammatory cytokines, rendering them highly responsive to signals emanating from inflamed sites during disease (King and Goodell, 2011; Takizawa et al, 2012). IL-6 (McCranor et al, 2014), TNF-α (Xiao et al, 2002), and IFN-γ (Felli et al, 2005; Libregts et al, 2011) have exerted suppressive effects on erythropoiesis in various settings, but the relative importance of these and other as-yet-unknown factors in causing AID, and the progenitor stages on which they act, remain unclear
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