2. Academic Validation
  3. The Trim32-DPEP2 axis is an inflammatory switch in macrophages during intestinal inflammation

The Trim32-DPEP2 axis is an inflammatory switch in macrophages during intestinal inflammation

  • Cell Death Differ. 2025 Jul;32(7):1336-1352. doi: 10.1038/s41418-025-01468-w.
Zhiyan Zhan # 1 2,  Huisheng Liang # 3 4,  Zhuoqi Zhao # 5,  Liya Pan 5,  Jing Li 5,  Yuyun Chen 6,  Zhoulonglong Xie 7,  Zhilong Yan 8,  Ying Xiang 9,  Wenxue Liu 10,  Li Hong 11
Affiliations

Affiliations

  • 1 Department of Clinical Nutrition, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China. zhanzhiyan@sjtu.edu.cn.
  • 2 Clinical Research Center, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China. zhanzhiyan@sjtu.edu.cn.
  • 3 Department of Obstetrics and Gynecology, Zhongshan Hospital, Fudan University, Shanghai, China.
  • 4 Department of Gynecology, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, 361000, China.
  • 5 Department of Clinical Nutrition, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China.
  • 6 Fujian Children's Hospital (Fujian Branch of Shanghai Children's Medical Center), College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, China.
  • 7 Department of Surgery, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China.
  • 8 Department of Surgery, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China. dryanzhilong@163.com.
  • 9 Department of Laboratory Medicine, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China. xiangying@scmc.com.cn.
  • 10 Department of Obstetrics and Gynecology, Zhongshan Hospital, Fudan University, Shanghai, China. liu.wenxue@zs-hospital.sh.cn.
  • 11 Department of Clinical Nutrition, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China. hongli@scmc.com.cn.
  • # Contributed equally.
PMID: 40021897 DOI: 10.1038/s41418-025-01468-w
Abstract

The mechanisms via which inflammatory macrophages mediate intestinal inflammation are not completely understood. Herein, using merged analysis of RNA Sequencing and mass spectrometry-based quantitative proteomics, we detected differences between proteomic and transcriptomic data in activated macrophages. Dipeptidase-2 (DPEP2), a member of the DPEP family, was highly expressed and then downregulated sharply at the protein level but not at the mRNA level in macrophages in response to inflammatory stimulation. Suppression of DPEP2 not only enhanced macrophage-mediated intestinal inflammation in vivo but also promoted the transduction of inflammatory pathways in macrophages in vitro. Mechanistically, overexpressed DPEP2 inhibited the transduction of inflammatory signals by resisting MAK3K7 in inactivated macrophages, whereas DPEP2 degradation by activated Trim32 resulted in strong activation of NF-κB and p38 MAPK signaling via the release of MAK3K7 in proinflammatory macrophages during the development of intestinal inflammation. The Trim32-DPEP2 axis accumulates the potential energy of inflammation in macrophages. These results identify DPEP2 as a key regulator of macrophage-mediated intestinal inflammation. Thus, the Trim32-DPEP2 axis may be a potential therapeutic target for the treatment of intestinal inflammation.

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