The Fifth Epidermal Growth Factor-like Region of Thrombomodulin Alleviates Murine Graft-versus-Host Disease in a G-Protein Coupled Receptor 15 Dependent Manner.
Thrombomodulin (TM) exerts anti-inflammatory functions. We previously found that recombinant human soluble TM alleviated murine graft-versus-host disease (GVHD). Nevertheless, it is unclear how TM mediates its anti-inflammatory functions in GVHD. Here, we identified G-protein coupled receptor 15 (GPR15) expressed on T cells as a receptor/sensor of TM. The fifth region of epidermal growth factor-like domain of TM (TME5) bound GPR15 in vitro. TME5 prolonged survival of mice undergoing acute GVHD after allogeneic hematopoietic stem cell transplantation (allo-HSCT). TME5 increased regulatory T cells (Tregs) but decreased Th 1 proportions in targeted organs. TME5 suppressed allo-reaction in vitro in association with an increase in the number of induced Tregs. However, the anti-inflammatory function of TME5 was abolished when GPR15 knockout T cells were used as donor T cells. We further found that TME5 suppressed production of IL-6 in T cells, which probably facilitated differentiation of Tregs. Moreover, TME5 reduced activation of bone marrow-derived dendritic cells (BMDCs) and hampered function of BMDCs in inducing allo-reaction in vivo and in vitro. Our findings suggested that inducing Tregs as well as blocking activation of DCs in vivo by using TME5 is a potential therapeutic option for preventing GVHD in allo-HSCT.
Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China; Department of Hematology and Respiratory Medicine, Kochi Medical School, Kochi University, Nankoku, Japan; Department of Hematology, Fukushima Medical University, Fukushima, Japan.
Bin
B
Pan
Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China; Department of Hematology and Respiratory Medicine, Kochi Medical School, Kochi University, Nankoku, Japan; Department of Hematology, Fukushima Medical University, Fukushima, Japan.
Xiangmin
X
Wang
Department of Hematology and Respiratory Medicine, Kochi Medical School, Kochi University, Nankoku, Japan.
Shinsuke
S
Kojima
Department of Hematology and Respiratory Medicine, Kochi Medical School, Kochi University, Nankoku, Japan; Department of Immunology, Kochi Medical School, Kochi University, Nankoku, Japan.
Chie
C
Nishioka
Department of Hematology and Respiratory Medicine, Kochi Medical School, Kochi University, Nankoku, Japan.
Akihito
A
Yokoyama
Medical Affairs Department, Asahi Kasei Pharma., Tokyo, Japan.
Goichi
G
Honda
Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China. Electronic address: lihmd@163.com.
Kailin
K
Xu
Department of Hematology and Respiratory Medicine, Kochi Medical School, Kochi University, Nankoku, Japan; Department of Hematology, Fukushima Medical University, Fukushima, Japan. Electronic address: ikezoet@fmu.ac.jp.
Takayuki
T
Ikezoe
D000818:Animals; D003713:Dendritic Cells / Q000187:drug effects; D004815:Epidermal Growth Factor; D006086:Graft vs Host Disease / Q000517:prevention & control*; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects; D006801:Humans; D007249:Inflammation / Q000188:drug therapy; D047589:Leukocyte Reduction Procedures / Q000379:methods; D051379:Mice; D010446:Peptide Fragments / Q000494:pharmacology* / Q000627:therapeutic use; D043562:Receptors, G-Protein-Coupled / Q000502:physiology*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology; D018180:Thrombomodulin / Q000627:therapeutic use*; D014184:Transplantation, Homologous
C523001:Gpr15 protein, mouse; D010446:Peptide Fragments; D043562:Receptors, G-Protein-Coupled; C546931:THBD protein, human; D018180:Thrombomodulin; D004815:Epidermal Growth Factor
G-protein coupled receptor 15; Graft-versus-host disease; Interleukin-6; Regulatory T cells; Thrombomodulin