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

Nat Immunol. 2021 Apr;22(4):520-529. doi: 10.1038/s41590-021-00895-4. Epub 2021 Mar 22.

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 (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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anemia / blood
  • Anemia / immunology
  • Anemia / metabolism*
  • Anemia / prevention & control
  • Animals
  • Antibodies, Neutralizing / pharmacology*
  • Cells, Cultured
  • Cellular Microenvironment
  • Disease Models, Animal
  • Erythroid Cells / immunology
  • Erythroid Cells / metabolism*
  • Erythropoiesis / drug effects*
  • Humans
  • Interleukins / antagonists & inhibitors*
  • Interleukins / immunology
  • Interleukins / metabolism
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myelodysplastic Syndromes / blood
  • Myelodysplastic Syndromes / drug therapy*
  • Myelodysplastic Syndromes / immunology
  • Myelodysplastic Syndromes / metabolism
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • 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

Substances

  • Antibodies, Neutralizing
  • Interleukins
  • Proto-Oncogene Proteins c-vav
  • Receptors, Interleukin
  • TP53 protein, human
  • Trp53 protein, mouse
  • Tumor Suppressor Protein p53
  • VAV1 protein, human
  • Vav1 protein, mouse
  • interleukin-22 receptor
  • Protein-Serine-Threonine Kinases
  • RIOK2 protein, human
  • interleukin-22