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mTOR Regulates Myc-Driven Acinar-to-Dendritic Cell Transition and the CD4 + T Cell Immune Response in Acute Pancreatitis

26 Pages Posted: 12 Jan 2020

See all articles by Dan Xu

Dan Xu

Shanghai Jiao Tong University (SJTU) - Department of General Surgery

Kaige Yang

Shanghai Jiao Tong University (SJTU) - Department of General Surgery

Rongli Xie

Shanghai Jiao Tong University (SJTU) - Department of General Surgery

Zhifeng Zhao

Shanghai Jiao Tong University (SJTU)

Min Ding

Shanghai Jiao Tong University (SJTU)

Wei Chen

Shanghai Jiao Tong University (SJTU) - Department of General Surgery

Jun Zhang

Shanghai Jiao Tong University (SJTU) - Department of General Surgery

Enqiang Mao

Shanghai Jiao Tong University (SJTU) - Department of Emergency

Erzhen Chen

Shanghai Jiao Tong University (SJTU) - Department of Emergency

Ying Chen

Shanghai Jiao Tong University (SJTU) - Department of Emergency

Zhiwei Xu

Shanghai Jiao Tong University (SJTU) - Department of General Surgery

Tong Zhou

Shanghai Jiao Tong University (SJTU) - Department of Pediatrics

Jian Fei

Shanghai Jiao Tong University (SJTU) - Department of General Surgery

More...

Abstract

Background: The inflammatory response in acute pancreatitis (AP) is associated with acinar-to-dendritic cell transition. The CD4+T cell-mediated adaptive immune response is necessary for pancreatic inflammatory damage. However, the effect of acinar-to-dendritic cell transition on the CD4+T cell response and the regulatory mechanism remain undefined.

Methods: An animal model of AP was established by repeated intraperitoneal injection of caerulein. The mTOR inhibitor rapamycin was administered before AP induction. Primary acinar cells were isolated and co-incubated with subsets of differentiated CD4+T cells. Flow cytometry was used to detect the differentiation of naive CD4+T cells. The transcriptional regulatory effect of Myc on DC-SIGN was determined via a luciferase assay. The expression of DC-SIGN was also assessed in pancreatic tissues from human AP patients.

Findings: Acinar cells expressed DC-SIGN and displayed the phenotype of dendritic cells (DCs), which promoted the differentiation of naive CD4+T cells into CD4+/IFN-γ+Th1 and CD4+/IL-17A+Th17 cells in pancreatic tissues during AP. DC-SIGN was the target gene of Myc. The mTOR inhibitor rapamycin inhibited AP-induced DC-SIGN expression, CD4+Th1/Th17 cell differentiation and the pro-inflammatory response via Myc. Acinar cells expressed DC-SIGN in pancreatic tissues of human patients with AP.

Interpretation: Acinar-to-dendritic cell transition is implicated in the CD4+T cell immune response via the mTOR-Myc-DC-SIGN axis, which might be an effective target for the prevention of local pancreatic inflammation in AP.

Funding Statement: This research was financially supported by the Natural Science Foundation of China (Nos. 81270801, 81470941, 81670581 and 8167030165), Program for Outstanding Medical Academic Leader and Shanghai Municipal Science and Technology Commission (No. 18411966400).

Declaration of Interests: The authors declare that they have no conflicts of interest.

Ethics Approval Statement: All patient biopsy samples were approved by Ruijin Hospital Ethics Committee.

Animal procedures were approved by the Shanghai Jiao Tong University School of Medicine Institutional Animal Care and Use Committee.

Keywords: mTOR, Myc, DC-SIGN, Acinar cells, CD4+ T cells

Suggested Citation

Xu, Dan and Yang, Kaige and Xie, Rongli and Zhao, Zhifeng and Ding, Min and Chen, Wei and Zhang, Jun and Mao, Enqiang and Chen, Erzhen and Chen, Ying and Xu, Zhiwei and Zhou, Tong and Fei, Jian, mTOR Regulates Myc-Driven Acinar-to-Dendritic Cell Transition and the CD4 + T Cell Immune Response in Acute Pancreatitis (January 6, 2020). Available at SSRN: https://ssrn.com/abstract=3514625 or http://dx.doi.org/10.2139/ssrn.3514625

Dan Xu

Shanghai Jiao Tong University (SJTU) - Department of General Surgery

Shanghai
China

Kaige Yang

Shanghai Jiao Tong University (SJTU) - Department of General Surgery

Shanghai
China

Rongli Xie

Shanghai Jiao Tong University (SJTU) - Department of General Surgery

Shanghai
China

Zhifeng Zhao

Shanghai Jiao Tong University (SJTU)

KoGuan Law School
Shanghai 200030, Shanghai 200052
China

Min Ding

Shanghai Jiao Tong University (SJTU)

KoGuan Law School
Shanghai 200030, Shanghai 200052
China

Wei Chen

Shanghai Jiao Tong University (SJTU) - Department of General Surgery

Shanghai
China

Jun Zhang

Shanghai Jiao Tong University (SJTU) - Department of General Surgery

Shanghai
China

Enqiang Mao

Shanghai Jiao Tong University (SJTU) - Department of Emergency

Shanghai, 200025
China

Erzhen Chen

Shanghai Jiao Tong University (SJTU) - Department of Emergency

Shanghai, 200025
China

Ying Chen

Shanghai Jiao Tong University (SJTU) - Department of Emergency ( email )

Shanghai, 200025
China

Zhiwei Xu

Shanghai Jiao Tong University (SJTU) - Department of General Surgery ( email )

Shanghai
China

Tong Zhou

Shanghai Jiao Tong University (SJTU) - Department of Pediatrics ( email )

Shanghai
China

Jian Fei (Contact Author)

Shanghai Jiao Tong University (SJTU) - Department of General Surgery ( email )

Shanghai
China

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