Monocytes generated by interleukin-6-treated human hematopoietic stem and progenitor cells secrete calprotectin that inhibits erythropoiesis

Elevated circulating levels of calprotectin (CAL), the S100A8/A9 heterodimer, are biomarkers of severe systemic inflammation. Here, we investigate the effects of CAL on early human hematopoiesis. CAL demonstrates limited impact on gene expression in stem and progenitor cells, in contrast with interleukin-6 (IL6), which promotes the expression of the S100A8 and S100A9 genes in hematopoietic progenitors and the generation of monocytes that release CAL. The main target of CAL is an erythroid-megakaryocyte progenitor (EMP) subset. CAL prevents both erythropoietin-driven differentiation of healthy progenitors and JAK2-V617F-driven erythropoiesis. In the context of JAK2-V617F, CAL also promotes the expression of S100A8 and S100A9 genes in monocytes. The signature of CAL effects is detected in the bone marrow progenitors of patients with myeloid malignancy or severe infection. These results position CAL as a mediator of IL6 effects on triggering anemia during inflammation, an effect that is amplified in the context of JAK2-V617F-driven hematopoiesis.