Blockade of IL-22 signaling reverses erythroid dysfunction in stress-induced anemias.

Abstract

Patients with myelodysplastic syndromes (MDS) display severe anemia but the mechanisms underlying this phenotype are incompletely understood. Right open-reading-frame kinase 2 (RIOK2) encodes a protein kinase located at 5q15, a region frequently lost in MDS del(5q) patients. Here, we show that hematopoietic cell-specific haploinsufficient deletion of Riok2 (Riok2f/+Vav1cre) led to reduced erythroid precursor frequency leading to anemia. Proteomic analysis of Riok2f/+Vav1cre erythroid precursors suggested immune system activation and transcriptomic analysis revealed an increase in p53-dependent interleukin-22 (IL-22) in Riok2f/+Vav1cre CD4+ T cells (TH22). Further, we discovered that the IL-22 receptor, IL-22RA1, was unexpectedly present on erythroid precursors. Blockade of IL-22 signaling alleviated anemia not only in Riok2f/+Vav1cre mice but also in wild-type mice. Serum concentrations of IL-22 were increased in the subset of del(5q) MDS patients as well as patients with anemia secondary to chronic kidney disease (CKD). This work reveals a possible therapeutic opportunity for reversing many stress-induced anemias by targeting IL-22 signaling.