Interleukin-33 contributes to anemia of chronic inflammation by inhibiting differentiation of erythroid progenitors

Mature blood cells are produced continuously from hematopoietic stem and progenitor cells (HSPCs) in the bone marrow (BM). During chronic inflammation, this process may be perturbed by inflammatory cytokines acting on HSPCs to cause anemia of inflammatory disease. Among BM HSPCs, we found the receptor for interleukin (IL)-33, ST2, was 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 showed that IL-33 directly inhibited terminal maturation. This effect was dependent on NF-kB activation and was associated with altered signalling events downstream of the erythropoietin receptor. Accordingly, IL-33 also suppressed erythropoietin-induced stress erythropoiesis in vivo. These results reveal a role for IL-33 in regulation of erythropoiesis during inflammatory disease and define a new target for its treatment. Overall design: RNA-seq of purified erythroid progenitors treated with IL33 or vehicle.

成熟血细胞持续由骨髓（bone marrow, BM）中的造血干祖细胞（hematopoietic stem and progenitor cells, HSPCs）产生。慢性炎症状态下，该造血过程可被作用于HSPCs的炎性细胞因子扰乱，进而引发炎症性贫血。我们在骨髓HSPCs中发现，白细胞介素（interleukin, IL）-33的受体ST2在红系祖细胞上呈优先高表达模式。给小鼠诱导炎性脊柱关节炎后，其骨髓血浆中的IL-33水平显著升高，且IL-33是炎症依赖性骨髓红系生成抑制所必需的关键分子。反之，向健康小鼠施用IL-33可抑制红系生成、降低血红蛋白表达水平并诱发贫血。通过体外纯化红系祖细胞实验，我们证实IL-33可直接阻断红系终末成熟，该效应依赖核因子κB（NF-κB）激活，且与促红细胞生成素受体下游的信号转导事件改变密切相关。相应地，IL-33在体内也可抑制促红细胞生成素诱导的应激性红系生成。本研究结果揭示了IL-33在炎性疾病期间调控红系生成的关键作用，并为该类疾病的治疗定义了全新靶点。整体实验设计：经IL33或溶剂处理的纯化红系祖细胞的RNA测序（RNA-seq）。