1. Survival signal REG3α prevents crypt apoptosis to control acute gastrointestinal graft-versus-host disease.
- Author
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Zhao D, Kim YH, Jeong S, Greenson JK, Chaudhry MS, Hoepting M, Anderson ER, van den Brink MR, Peled JU, Gomes AL, Slingerland AE, Donovan MJ, Harris AC, Levine JE, Ozbek U, Hooper LV, Stappenbeck TS, Ver Heul A, Liu TC, Reddy P, and Ferrara JL
- Subjects
- Animals, Cell Survival genetics, Colon pathology, Female, Graft vs Host Disease pathology, Humans, Inflammatory Bowel Diseases genetics, Inflammatory Bowel Diseases pathology, Male, Mice, Mice, Inbred BALB C, Mice, Knockout, Pancreatitis-Associated Proteins genetics, Paneth Cells pathology, Prospective Studies, Transplantation, Homologous, Apoptosis, Bone Marrow Transplantation, Colon metabolism, Graft vs Host Disease metabolism, Inflammatory Bowel Diseases metabolism, Pancreatitis-Associated Proteins metabolism, Paneth Cells metabolism, Signal Transduction
- Abstract
Graft-versus-host disease (GVHD) in the gastrointestinal (GI) tract remains the major cause of morbidity and nonrelapse mortality after BM transplantation (BMT). The Paneth cell protein regenerating islet-derived 3α (REG3α) is a biomarker specific for GI GVHD. REG3α serum levels rose in the systematic circulation as GVHD progressively destroyed Paneth cells and reduced GI epithelial barrier function. Paradoxically, GVHD suppressed intestinal REG3γ (the mouse homolog of human REG3α), and the absence of REG3γ in BMT recipients intensified GVHD but did not change the composition of the microbiome. IL-22 administration restored REG3γ production and prevented apoptosis of both intestinal stem cells (ISCs) and Paneth cells, but this protection was completely abrogated in Reg3g-/- mice. In vitro, addition of REG3α reduced the apoptosis of colonic cell lines. Strategies that increase intestinal REG3α/γ to promote crypt regeneration may offer a novel, nonimmunosuppressive approach for GVHD and perhaps for other diseases involving the ISC niche, such as inflammatory bowel disease.
- Published
- 2018
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