2. Academic Validation
  3. Neddylation pathway alleviates chronic pancreatitis by reducing HIF1α-CCL5-dependent macrophage infiltration

Neddylation pathway alleviates chronic pancreatitis by reducing HIF1α-CCL5-dependent macrophage infiltration

  • Cell Death Dis. 2021 Mar 15;12(3):273. doi: 10.1038/s41419-021-03549-3.
Yuli Lin  # 1 2,  Yusheng Chen  # 3,  Wenxue Feng  # 4,  Rong Hua 5,  Junfeng Zhang 5,  Yanmiao Huo 5,  Hong Jiang 6,  Bo Yin 7,  Xuguang Yang 8
Affiliations

Affiliations

  • 1 Clinical Research Center, Department of Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China. yulilin@fudan.edu.cn.
  • 2 Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China. yulilin@fudan.edu.cn.
  • 3 Department of Pancreatic Surgery, Department of Oncology, Pancreatic Cancer Institute, Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, China.
  • 4 Department of Radiology, Huashan Hospital, Fudan University, Shanghai, China.
  • 5 Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
  • 6 Department of General Surgery, Huadong Hospital, Fudan University, Shanghai, China.
  • 7 Department of Radiology, Huashan Hospital, Fudan University, Shanghai, China. yinbo7@163.com.
  • 8 Clinical Research Center, Department of Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China. xuguangyang11@fudan.edu.cn.
  • # Contributed equally.
PMID: 33723230 DOI: 10.1038/s41419-021-03549-3
Abstract

Chronic pancreatitis (CP) is characterized by a wide range of irreversible fibro-inflammatory diseases with largely ambiguous pathogenesis. Although neddylation pathway has been implicated in regulating immune responses, whether the dysregulation of neddylation is involved in the progression of CP and how neddylation regulates the inflammatory microenvironment of CP have not yet been reported. Here, we demonstrate that global inactivation of neddylation pathway by MLN4924 significantly exacerbates chronic pancreatitis. The increased M2 macrophage infiltration, mediated by the upregulated chemokine (C-C motif) ligand 5 (CCL5), is responsible for the enhanced pancreatitis-promoting activity of MLN4924. Both CCL5 blockade and macrophage depletion contribute to alleviating pancreatic fibrosis and inflammation in MLN4924-treated CP mice. Mechanistic investigation identifies that inactivation of Cullin-RING ligases (CRLs) stabilizes cellular levels of hypoxia-inducible factor 1α (HIF-1α), which increases CCL5 expression by promoting CCL5 transactivation. Clinically, UBE2M expression remarkably decreases in human CP tissues compared with normal specimens and the levels of CCL5 and M2 marker CD163 are negatively correlated with UBE2M intensity, suggesting that neddylation is involved in the pathogenesis of pancreatitis. Hence, our studies reveal a neddylation-associated immunopathogenesis of chronic pancreatitis and provide new ideas for the disease treatment.

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