Journal Article

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

Glimcher, Laurie H., Ghosh, Shrestha, Regev, Aviv, Myers, Samuel A., Carr, Steven A., Cuoco, Michael S., Bonventre, Joseph V., Stone, Richard M., Steensma, David P., Waikar, Sushrut S., Raundhal, Mahesh, Singer, Meromit, Ritz, Jerome

2021

Overview

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 H 22). 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/250/127/1210 / 692/420/256/2515 / Anemia / Anemia - blood / Anemia - immunology / Anemia - metabolism / Anemia - prevention & control / Animals / Antibodies, Neutralizing - pharmacology / Biomedical and Life Sciences / Biomedicine / Care and treatment / CD4 antigen / Cells, Cultured / Cellular Microenvironment / Cellular signal transduction / Clonal deletion / Development and progression / Disease Models, Animal / Erythroid Cells - immunology / Erythroid Cells - metabolism / Erythropoiesis / Erythropoiesis - drug effects / Genetic aspects / Health aspects / Hemopoiesis / Humans / Immune system / Immunology / Infectious Diseases / Interleukin 22 / Interleukins / Interleukins - antagonists & inhibitors / Interleukins - immunology / Interleukins - metabolism / Kidney diseases / Kinases / Lymphocytes T / Mice, Inbred C57BL / Mice, Knockout / Myelodysplastic syndrome / Myelodysplastic syndromes / Myelodysplastic Syndromes - blood / Myelodysplastic Syndromes - drug therapy / Myelodysplastic Syndromes - immunology / Myelodysplastic Syndromes - metabolism / p53 Protein / Phenotypes / Protein kinase / Protein Serine-Threonine Kinases - genetics / Protein Serine-Threonine Kinases - metabolism / Protein-serine/threonine kinase / Proteomics / Proto-Oncogene Proteins c-vav - genetics / Proto-Oncogene Proteins c-vav - metabolism / Receptors, Interleukin - genetics / Receptors, Interleukin - metabolism / Renal Insufficiency, Chronic - blood / Renal Insufficiency, Chronic - immunology / Renal Insufficiency, Chronic - metabolism / Signal Transduction / Tumor Suppressor Protein p53 - genetics / Tumor Suppressor Protein p53 - metabolism