2. Academic Validation
  3. Hyperglycemia-triggered lipid peroxidation destabilizes STAT4 and impairs anti-viral Th1 responses in type 2 diabetes

Hyperglycemia-triggered lipid peroxidation destabilizes STAT4 and impairs anti-viral Th1 responses in type 2 diabetes

  • Cell Metab. 2024 Dec 3;36(12):2511-2527.e7. doi: 10.1016/j.cmet.2024.10.004.
Victor Gray 1,  Weixin Chen 1,  Rachael Julia Yuenyinn Tan 1,  Jia Ming Nickolas Teo 1,  Zhihao Huang 2,  Carol Ho-Yi Fong 3,  Tommy Wing Hang Law 3,  Zi-Wei Ye 1,  Shuofeng Yuan 4,  Xiucong Bao 1,  Ivan Fan-Ngai Hung 3,  Kathryn Choon-Beng Tan 5,  Chi-Ho Lee 6,  Guang Sheng Ling 7
Affiliations

Affiliations

  • 1 School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
  • 2 Department of Chemistry, Faculty of Science, The University of Hong Kong, Hong Kong SAR, China.
  • 3 Department of Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, China.
  • 4 Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, China; State Key Laboratory of Emerging Infectious Diseases, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.
  • 5 Department of Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, China. Electronic address: kcbtan@hku.hk.
  • 6 Department of Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, China. Electronic address: pchlee@hku.hk.
  • 7 School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China; Department of Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, China; The University of Hong Kong-Shenzhen Hospital, Shenzhen, Guangdong, China. Electronic address: gsling@hku.hk.
PMID: 39488214 DOI: 10.1016/j.cmet.2024.10.004
Abstract

Patients with type 2 diabetes (T2D) are more susceptible to severe respiratory viral infections, but the underlying mechanisms remain elusive. Here, we show that patients with T2D and coronavirus disease 2019 (COVID-19) infections, and influenza-infected T2D mice, exhibit defective T helper 1 (Th1) responses, which are an essential component of anti-viral immunity. This defect stems from intrinsic metabolic perturbations in CD4+ T cells driven by hyperglycemia. Mechanistically, hyperglycemia triggers mitochondrial dysfunction and excessive fatty acid synthesis, leading to elevated oxidative stress and aberrant lipid accumulation within CD4+ T cells. These abnormalities promote lipid peroxidation (LPO), which drives carbonylation of signal transducer and activator of transcription 4 (STAT4), a crucial Th1-lineage-determining factor. Carbonylated STAT4 undergoes rapid degradation, causing reduced T-bet induction and diminished Th1 differentiation. LPO scavenger ameliorates Th1 defects in patients with T2D who have poor glycemic control and restores viral control in T2D mice. Thus, this hyperglycemia-LPO-STAT4 axis underpins reduced Th1 activity in T2D hosts, with important implications for managing T2D-related viral complications.

Keywords

T helper 1 responses; hyperglycemia; lipid peroxidation; protein carbonylation; type 2 diabetes.

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