IL-22 Accelerates Thymus Regeneration via Stat3/Mcl-1 and Decreases Chronic Graft-versus-Host Disease in Mice after Allotransplants

  • Biol Blood Marrow Transplant. 2019 Oct;25(10):1911-1919. doi: 10.1016/j.bbmt.2019.06.002.
Bin Pan  1 ,  Dong Wang  2 ,  Lingling Li  2 ,  Longmei Shang  2 ,  Fan Xia  2 ,  Fan Zhang  2 ,  Ying Zhang  3 ,  Robert Peter Gale  4 ,  Mengdi Xu  1 ,  Zhenyu Li  1 ,  Kailin Xu  5
Affiliations
  • 1. Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China; Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, Xuzhou, China.
  • 2. Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China.
  • 3. Department of Pathology, Xuzhou Medical University, Xuzhou, China.
  • 4. Centre for Haematology Research, Division of Experimental Medicine, Department of Medicine, Imperial College London, London, United Kingdom.
  • 5. Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China; Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, Xuzhou, China. Electronic address: [email protected].
PMID: 31195136 DOI: 10.1016/j.bbmt.2019.06.002
Abstract

High-dose chemotherapy and/or radiation given before an allogeneic hematopoietic cell transplantation severely damage thymic epithelial cells (TECs), resulting in poor post-transplant immune recovery. IL-22 mediates recovery of TECs via a proregenerative effect, but the precise mechanism by which this occurs is unknown. In this study, we found IL-22 improved thymus recovery after damage from irradiation in association with increased number of TECs. This effect was blocked by ruxolitinib, a JAK1/JAK2 Inhibitor. IL-22 increased the number of TECs via a Stat3-dependent signaling in the mTEC1 murine thymic epithelial cell line. This, in turn, upregulated transcription of myeloid cell leukemia sequence 1 (Mcl1), resulting in increased number of TECs. Similar effects were seen in irradiated mice given IL-22. Defects in IL-22 resulted in delayed thymus recovery in irradiated mice and had an impact on levels of thymus function-related genes such as Foxn1, Aire, and Kgf. In mice, post-transplant use of IL-22 improved repair of TECs, increased the numbers of thymus T cells, increased the intrathymic levels of Aire, and increased the proportion of natural regulatory T cells, resulting in decreased severity of chronic graft-versus-host disease (GVHD). Our data highlight the critical role of the IL-22/STAT3/Mcl-1 pathway in the regeneration of TECs after damage from irradiation in mice and highlight circumstances where normalizing thymus T cell function with IL-22 decreases GVHD after allotransplants.

Keywords
Graft-versus-host disease; IL-22; Thymic epithelial cell; Thymus.
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