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

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

doi:10.1172/jci99261

Cited by 102 publications

(98 citation statements)

References 38 publications

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“…In addition to the preceding discussion of myeloid/neutrophil markers of S100A 8/9 family members, these genes have been reported to be overexpressed in human PCa cells and their ectopic overexpression enhanced infiltration of immune cells, especially neutrophils, and stimulated metastatic seeding of the PCa cells in the lung 27 . Regenerating islet‐derived protein 3‐gamma (Reg3g) has been associated with colonic Paneth cell stemness and survival 28 . Two recent studies have revealed a novel immunosuppression role of Reg3g that weakens tumor‐specific antigenicity and suppresses antitumor effects of CD8+ T cells in murine models of pancreatic cancer, by activating the JAK2/STAT3 signaling pathway in DCs 29,30 .…”

Section: Discussionmentioning

confidence: 95%

“…27 Regenerating isletderived protein 3-gamma (Reg3g) has been associated with colonic Paneth cell stemness and survival. 28 Two recent studies have revealed a novel immunosuppression role of Reg3g that weakens tumor-specific antigenicity and suppresses antitumor effects of CD8+ T cells in murine models of pancreatic cancer, by activating the JAK2/STAT3 signaling pathway in DCs. 29,30 Lipocalin-2/NGAL has F I G U R E 3 Quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR) detection of mRNA of selected genes/ proteins normalized to β-actin for validation of proteomic and microarray platforms.…”

Section: Validation Of Differential Expression Of Selected Genes Anmentioning

confidence: 99%

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Proteomic and transcriptomic profiling of Pten gene‐knockout mouse model of prostate cancer

Zhang

Kim

et al. 2020

The Prostate

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Background The prostate‐specific phosphatase and tensin homolog deleted on chromosome 10 (Pten) gene‐conditional knockout (KO) mouse carcinogenesis model is highly desirable for studies of prostate cancer biology and chemoprevention due to its close resemblance of primary molecular defect and many histopathological features of human prostate cancer including androgen response and disease progression from prostatic intraepithelial neoplasia to invasive adenocarcinoma. Here, we profiled the proteome and transcriptome of the Pten‐KO mouse prostate tumors for global macromolecular expression alterations for signaling changes and biomarker signatures. Methods For proteomics, four pairs of whole prostates from tissue‐specific conditional knockout Pten‐KO mice (12‐15 weeks of age) and their respective wild‐type littermates housed in the same cages were analyzed by 8‐plex isobaric tags for relative and absolute quantitation iTRAQ. For microarray transcriptomic analysis, three additional matched pairs of prostate/tumor specimens from respective mice at 20 to 22 weeks of age were used. Real‐time quantitative reverse transcription‐polymerase chain reaction was used to verify the trends of protein and RNA expression changes. Gene Set Enrichment Analysis and Ingenuity Pathway Analysis were carried out for bioinformatic characterizations of pathways and networks. Results At the macromolecular level, proteomic and transcriptomic analyses complement and cross‐validate to reveal overexpression signatures including inflammation and immune alterations, in particular, neutrophil/myeloid lineage suppressor cell features, chromatin/histones, ion and nutrient transporters, and select glutathione peroxidases and transferases in Pten‐KO prostate tumors. Suppressed expression patterns in the Pten‐KO prostate tumors included glandular differentiation such as secretory proteins and androgen receptor targets, smooth muscle features, and endoplasmic reticulum stress proteins. Bioinformatic analyses identified immune and inflammation responses as the most profound macromolecular landscape changes, and the predicted key nodal activities through Akt, nuclear factor‐kappaB, and P53 in the Pten‐KO prostate tumor. Comparison with other genetically modified mouse prostate carcinogenesis models revealed notable molecular distinctions, especially the dominance of immune and inflammation features in the Pten‐KO prostate tumors. Conclusions Our work identified prominent macromolecular signatures and key nodal molecules that help to illuminate the patho‐ and immunobiology of Pten‐loss driven prostate cancer and can facilitate the choice of biomarkers for chemoprevention and interception studies in this clinically relevant mouse prostate cancer model.

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Section: Discussionmentioning

confidence: 95%

Section: Validation Of Differential Expression Of Selected Genes Anmentioning

confidence: 99%

Proteomic and transcriptomic profiling of Pten gene‐knockout mouse model of prostate cancer

Zhang

Kim

et al. 2020

The Prostate

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“…In the intestine, IL-22 from intestinal ILC3 cells supports intestinal epithelial regeneration and barrier function (Hanash et al, 2012; Lindemans et al, 2015). When tested in preclinical models of acute GVHD, treatment with recombinant IL-22 generally improved the disease, increased numbers of Lgr5 + stem cells, enhanced expression of antimicrobial peptides Reg3α and Reg3γ, and improved epithelial integrity (Lindemans et al, 2015; Zhao et al, 2018). The beneficial effect of IL-22 is not limited to the intestine, as IL-22 is also critical for the regeneration and survival of thymic epithelial cells (Dudakov et al, 2017; Pan et al, 2019).…”

Section: Gvhdmentioning

confidence: 99%

“…As discussed above, Reg3α and Reg3γ can be secreted by IECs upon IL-22 stimulation (Zheng et al, 2008). Elevated serum Reg3α is a prognostic biomarker of severe intestinal GVHD, which occurs in 9–15% of patients receiving allogeneic hematopoietic transplantation (Ferrara et al, 2011; Zhao et al, 2018). Likely, increased serum Reg3α levels reflect a more severely damaged intestinal barrier, which would predispose patients to more severe intestinal GVHD.…”

Section: Gvhdmentioning

confidence: 99%

The role of IL-22 in intestinal health and disease

Keir¹,

Yi²,

Lu³

et al. 2020

Journal of Experimental Medicine

242

143

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The cytokine interleukin-22 (IL-22) is a critical regulator of epithelial homeostasis. It has been implicated in multiple aspects of epithelial barrier function, including regulation of epithelial cell growth and permeability, production of mucus and antimicrobial proteins (AMPs), and complement production. In this review, we focus specifically on the role of IL-22 in the intestinal epithelium. We summarize recent advances in our understanding of how IL-22 regulates homeostasis and host defense, and we discuss the IL-22 pathway as a therapeutic target in diseases of the intestine, including inflammatory bowel disease (IBD), graft-versus-host disease (GVHD), and cancer.

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“…Regenerating Islet-derived 3-alpha (Reg3α) has been validated as a prognostic and diagnostic biomarker specific to gastrointestinal aGvHD. Increased serum Reg3α levels post-transplantation have shown to indicate an increased incidence of severe aGvHD, thought to be caused by the destruction of GI paneth cells and impaired epithelial function (22), which was also indicative of poor prognosis following treatment (23). A 2 biomarker panel based algorithm combining ST2 and Reg3α levels measured 7 days post-transplant has been shown to stratify patients on the basis of NRM into two distinct high risk and low risk groups (24).…”

Section: Biomarkers In Agvhdmentioning

confidence: 99%

Extracorporeal Photopheresis (ECP) and the Potential of Novel Biomarkers in Optimizing Management of Acute and Chronic Graft vs. Host Disease (GvHD)

et al. 2020

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As the use of hematopoietic stem cell transplantation (HSCT) has become a more widespread and effective treatment for hematological malignant and non-malignant conditions, the need to minimize the harmful effects of graft-vs.-host disease (GvHD) has become more important in achieving good outcomes. With diagnosis of GvHD reliant on its clinical manifestations, research into biomarkers for the diagnosis, progression, and even for the prediction of disease, is imperative to combating the high levels of morbidity and mortality post-HSCT. Despite the development of novel treatment approaches to GvHD, corticosteroids remain the standard first-line treatment, with immunosuppressant therapies as second-line options. These strategies however have significant limitations and associated complications. Extracorporeal Photopheresis (ECP) has shown to be effective and safe in treating patients with symptomatic GvHD. ECP has been shown to have varied effects on multiple parts of the immune system and does not appear to increase the risk of relapse or infection in the post HSCT setting. Even so, ECP can be logistically more complex to organize and requires patients to be sufficiently stable. This review aims to summarize the potential role of biomarkers to help guide individualized treatment decisions in patients with acute and chronic GvHD. In relation to ECP, robust biomarkers of GvHD will be highly useful in informing patient selection, intensity and duration of the ECP schedule, monitoring of response and other treatment decisions alongside the concurrent administration of other GvHD therapies. Further research is warranted to establish how GvHD biomarkers are best incorporated into ECP treatment pathways with the goal of tailoring ECP to the needs of individual patients and maximizing benefit.

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

Cited by 102 publications

References 38 publications

Proteomic and transcriptomic profiling of Pten gene‐knockout mouse model of prostate cancer

Proteomic and transcriptomic profiling of Pten gene‐knockout mouse model of prostate cancer

The role of IL-22 in intestinal health and disease

Extracorporeal Photopheresis (ECP) and the Potential of Novel Biomarkers in Optimizing Management of Acute and Chronic Graft vs. Host Disease (GvHD)

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