Survival signal REG3α prevents crypt apoptosis to control acute gastrointestinal graft-versus-host disease
Dongchang Zhao, … , Pavan Reddy, James L.M. Ferrara
Dongchang Zhao, … , Pavan Reddy, James L.M. Ferrara
Published November 1, 2018; First published August 14, 2018
Citation Information: J Clin Invest. 2018;128(11):4970-4979. https://doi.org/10.1172/JCI99261.
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Categories: Concise Communication Immunology Transplantation

Survival signal REG3α prevents crypt apoptosis to control acute gastrointestinal graft-versus-host disease

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.

Authors

Dongchang Zhao, Yeung-Hyen Kim, Seihwan Jeong, Joel K. Greenson, Mohammed S. Chaudhry, Matthias Hoepting, Erik R. Anderson, Marcel R.M. van den Brink, Jonathan U. Peled, Antonio L.C. Gomes, Ann E. Slingerland, Michael J. Donovan, Andrew C. Harris, John E. Levine, Umut Ozbek, Lora V. Hooper, Thaddeus S. Stappenbeck, Aaron Ver Heul, Ta-Chiang Liu, Pavan Reddy, James L.M. Ferrara

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Figure 4

REG3γ absence increases GVHD severity.

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REG3γ absence increases GVHD severity. WT B6 and B6-Reg3g–/– (KO) mice u...
WT B6 and B6-Reg3g–/– (KO) mice underwent BMT from B6-Ly5.1 donors (GVHD –: WT, white circles; KO, white squares) or C3H.SW donors (GVHD +: WT, black circles; KO, red squares). (A–C) Serial body weight measurement (A), clinical GVHD score (B), and survival (C) of mice after BMT (WT, white circles, n = 7; KO, white squares, n = 7; WT, black circles, n = 18; KO, red squares, n = 16). (D–F) On day +7 after BMT, WT or KO recipients (Lgr5-EGFP+) were euthanized. Small intestine crypt cells were isolated and analyzed by flow cytometry. Small intestine sections were stained by immunochemistry. (D and E) Quantification of Paneth cells (D) and quantification of Paneth cells undergoing early apoptosis by annexin V+ staining (E) (WT, white circles, n = 6; KO, white squares, n = 6; WT, black circles, n = 8; KO, red squares, n = 8). (F) Quantification of cleaved caspase-3+ cells per crypt of ileum sections in recipients (each group, n = 5). *P < 0.05, **P < 0.01, ***P < 0.001, unpaired 2-tailed t test (A, B, and D–F); **P < 0.01, log-rank test (C). Data are expressed as mean ± SEM. (G–I) Microbiome composition of fecal samples from WT and KO mice 1 day before BMT (Pre-BMT) (WT, white circles, n = 12; KO, white squares, n = 13) or day +7 after BMT (Post-BMT) (WT, black circles, n = 12; KO, red squares, n = 13). (G) Principal component analysis was computed from the Bray-Curtis β-diversity matrix among all samples. (H and I) Bray-Curtis compositional distances were measured from the centroid of WT pre-BMT samples (H) or post-BMT samples (I). NS, P > 0.05; *P < 0.05, **P < 0.01, Wilcox test.