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

• Main Authors: Raundhal, Mahesh (Author), Ghosh, Shrestha (Author), Myers, Samuel A (Author), Cuoco, Michael S (Author), Singer, Meromit (Author), Carr, Steven A (Author), Waikar, Sushrut S (Author), Bonventre, Joseph V (Author), Ritz, Jerome (Author), Stone, Richard M (Author), Steensma, David P (Author), Regev, Aviv (Author), Glimcher, Laurie H (Author)
• Format: Article
• Language: English
• Published: Springer Science and Business Media LLC, 2021-10-04T19:18:26Z.
• Subjects: Article
• Online Access: Get fulltext

 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 (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 (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 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.