2. Academic Validation
  3. Diabetes exacerbates myasthenia gravis by enhancing pathological thymic output via the GPR183-7α,25-OHC axis

Diabetes exacerbates myasthenia gravis by enhancing pathological thymic output via the GPR183-7α,25-OHC axis

  • J Neuroinflammation. 2025 Oct 29;22(1):250. doi: 10.1186/s12974-025-03571-8.
Jing Dong 1,  Xin Shi 1,  Xu-Dong Gu 2,  Ying Yang 3,  Yi-Lin He 1,  Yang Zhou 1 4 5,  Heng Li 1 4 5,  Tong Du 1 4 5,  Wei-Yue Si 6,  Shu-Li Wei 1,  Chang Liu 1,  Bing Yang 1 4 5,  Yan-Bin Li 1 4 5,  Rui-Sheng Duan 7 8 9,  Chun-Lin Yang 10 11 12,  Peng Zhang 13 14 15
Affiliations

Affiliations

  • 1 Department of Neurology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, 250014, People's Republic of China.
  • 2 College of First Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China.
  • 3 Department of Pharmacy, The Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250014, China.
  • 4 Shandong Institute of Neuroimmunology, Jinan, 250014, People's Republic of China.
  • 5 Shandong Provincial Medicine and Health Key Laboratory of Neuroimmunology, Jinan, 250014, People's Republic of China.
  • 6 Department of Neurology, Cheeloo College of Medicine, Qilu Hospital, Shandong University, Jinan, 250012, Shandong, China.
  • 7 Department of Neurology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, 250014, People's Republic of China. ruisheng_duan@163.com.
  • 8 Shandong Institute of Neuroimmunology, Jinan, 250014, People's Republic of China. ruisheng_duan@163.com.
  • 9 Shandong Provincial Medicine and Health Key Laboratory of Neuroimmunology, Jinan, 250014, People's Republic of China. ruisheng_duan@163.com.
  • 10 Department of Neurology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, 250014, People's Republic of China. muyilin1991@163.com.
  • 11 Shandong Institute of Neuroimmunology, Jinan, 250014, People's Republic of China. muyilin1991@163.com.
  • 12 Shandong Provincial Medicine and Health Key Laboratory of Neuroimmunology, Jinan, 250014, People's Republic of China. muyilin1991@163.com.
  • 13 Department of Neurology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, 250014, People's Republic of China. peng03080308@126.com.
  • 14 Shandong Institute of Neuroimmunology, Jinan, 250014, People's Republic of China. peng03080308@126.com.
  • 15 Shandong Provincial Medicine and Health Key Laboratory of Neuroimmunology, Jinan, 250014, People's Republic of China. peng03080308@126.com.
PMID: 41163004 DOI: 10.1186/s12974-025-03571-8
Abstract

Background: Diabetes mellitus (DM) could exacerbate experimental autoimmune myasthenia gravis (EAMG) by affecting both the innate and adaptive immune systems, although the specific mechanism remains unclear. GPR183, a G protein-coupled receptor predominantly expressed on immune cells, contributes to autoimmune disease development by directing immune cell migration to secondary lymphoid organs. However, the correlation between GPR183 and MG has not been reported.

Methods: Researchers established a combined DM and EAMG model. Thymic immune cell and cytokine changes were assessed by flow cytometry. Transcriptomic profiles of sorted CD4+CD8− and CD4−CD8+ thymic T cells were analyzed via RNA Sequencing. Serum steroid Hormones were quantified by LC-MS/MS. The GPR183-7α,25-OHC pathway was evaluated using PCR, immunohistochemistry, and western blotting. In vivo blockade of GPR183 with inhibitor NIBR189 assessed its immune effects in EAMG rats with/without DM.

Results: Our study indicated that EAMG rats with DM exhibited more severe weight loss, thymus atrophy, and immune microenvironment alterations. Specifically, DM increased the percentages of mature and exported CD62L+ T cells in the thymus and peripheral blood of EAMG rats. RNA Sequencing revealed that diabetes promotes GPR183 expression on thymic T cells, primarily in the CD62L⁺ T cell subset in EAMG rats. DM activates the GPR183 ligand, elevates serum 7α,25-hydroxycholesterol levels, and enhances hepatic Cholesterol metabolism. GPR183 inhibition induces thymic T cell retention by selectively blocking CD62L⁺ T cell migration to the periphery. Moreover, GPR183 inhibitors weaken the adaptive immune function in DM + EAMG rats by expanding Treg cells, inhibiting Tfh/ASC differentiation, and reducing CD62L⁺ B cells.

Conclusion: Diabetes significantly upregulates thymic GPR183 (especially on CD62L⁺ T cells) and promotes synthesis of its ligand 7α,25-OHC via hepatic Cholesterol reprogramming, accelerating thymic T cells egress. This provides a novel therapeutic approach and a new perspective on how metabolic disorders reshape immune cell dynamics.

Supplementary Information: The online version contains supplementary material available at 10.1186/s12974-025-03571-8.

Keywords

7α,25-OHC; Diabetes mellitus (DM); GPR183; Myasthenia gravis (MG); Thymus.

Figures
Products