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

Abstract

Patients with myelodysplastic syndromes (MDSs) 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 patients with MDS del(5q). Here we show that hematopoietic cell-specific haploinsufficient deletion of Riok2 (Riok2^f/+Vav1^cre) led to reduced erythroid precursor frequency leading to anemia. Proteomic analysis of Riok2^f/+Vav1^cre erythroid precursors suggested immune system activation, and transcriptomic analysis revealed an increase in p53-dependent interleukin (IL)-22 in Riok2^f/+Vav1^cre CD4⁺ T cells (T_H22). 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 Riok2^f/+Vav1^cre mice but also in wild-type mice. Serum concentrations of IL-22 were increased in the subset of patients with del(5q) MDS as well as patients with anemia secondary to chronic kidney disease. This work reveals a possible therapeutic opportunity for reversing many stress-induced anemias by targeting IL-22 signaling.

Growing evidence suggests that immune dysregulation is involved in the pathogenesis of myelodysplastic syndromes (MDSs). Glimcher and colleagues report haplosufficiency of the serine–threonine kinase RIOK2 leads to increased IL-22 production that, in turn, suppresses erythropoiesis. Blocking IL-22 rescues this defect in mice, suggesting that IL-22 blockade might be of therapeutic value in treating MDSs.