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

Victor Gray1, Weixin Chen1, Rachael Julia Yuenyinn Tan1

  • 1School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.

Cell Metabolism
|November 2, 2024
PubMed

Insights

Type 2 diabetes impairs antiviral immunity by disrupting T helper 1 (Th1) cell responses. Hyperglycemia-induced metabolic defects lead to lipid peroxidation, damaging a key protein (STAT4) essential for Th1 function and increasing infection severity.

Area of Science:

  • Immunology
  • Metabolic disease
  • Virology

Background:

  • Patients with type 2 diabetes (T2D) face increased risk of severe respiratory viral infections.
  • Mechanisms linking T2D to impaired antiviral immunity are not fully understood.

Purpose of the Study:

  • Investigate the impact of T2D on T helper 1 (Th1) cell responses during viral infections.
  • Elucidate the molecular mechanisms underlying Th1 defects in T2D.

Main Methods:

  • Analysis of CD4+ T cells from T2D patients with COVID-19 and T2D mice infected with influenza.
  • Assessment of metabolic perturbations, mitochondrial function, oxidative stress, and lipid peroxidation in T cells.
  • Evaluation of STAT4 carbonylation, T-bet induction, and Th1 differentiation.
  • Testing the efficacy of a lipid peroxidation scavenger in T2D models.

Main Results:

  • T2D patients and mice show defective Th1 responses crucial for antiviral immunity.
  • Hyperglycemia in T2D CD4+ T cells causes mitochondrial dysfunction, oxidative stress, and lipid accumulation.
  • Lipid peroxidation leads to STAT4 carbonylation and degradation, impairing Th1 differentiation.
  • A lipid peroxidation scavenger improved Th1 function and viral control in T2D models.

Conclusions:

  • A hyperglycemia-lipid peroxidation-STAT4 axis impairs Th1 immunity in type 2 diabetes.
  • This pathway contributes to increased susceptibility to severe viral infections in T2D.
  • Targeting lipid peroxidation may offer therapeutic strategies for managing viral complications in T2D.
Keywords:
T helper 1 responseshyperglycemialipid peroxidationprotein carbonylationtype 2 diabetes

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