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TIPE2 knockout reduces myocardial cell damage by inhibiting IFN-γ-mediated ferroptosis
Yan Yang1, Yunhan Ma1, Shengnan Yu1
1Xiamen Key Laboratory of Regeneration Medicine, Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, Organ Transplantation Institute, School of Medicine, Xiamen University, Xiamen, China.
Abstract:
Acute rejection of the transplanted heart is mediated by oxidative programmed cell death through the synergistic effects of the innate and adaptive immune systems. However, the role of ferroptosis, a newly discovered form of oxidative cell death, has not been widely evaluated. Tumor necrosis factor-α-induced protein-8 like 2 (TNFAIP8L2), also known as TIPE2, is required for maintaining immune homeostasis. To characterize the role of TIPE2 in mediating heart allografts, BALB/c hearts were transplanted into C57BL/6 wild-type (WT) and TIPE2-/- recipient mice. In TIPE2-/- recipient mice, allograft injury in BALB/c allograft hearts was significantly reduced through the inhibition of allograft ferroptosis. On day 3 and day 6 post-transplantation, the numbers of CD3+, CD4+, and CD8+ cells among splenocytes and draining lymph node cells were significantly decreased, and the activation of CD4+ and CD8+ cells in grafts was decreased in TIPE2-/- recipient mice compared with WT mice. Moreover, CD4+ and CD8+ T cells in TIPE2-/- recipient mice were characterized by deficient capacities for interferon-γ (IFN-γ) production through the TBK1 signaling axis and increased glutathione peroxidase 4 (GPX4). In cell experiments, treatment with IFN-γ enhanced ferroptosis-specific lipid peroxidation in myocardial cells and correlated inversely with GPX4 expression. Mechanistically, IFN-γ administration decreased the expression of GPX4 by inhibiting MEK/ERK phosphorylation. In summary, our findings demonstrated that TIPE2 deficiency inhibits T-cell production of IFN-γ to reduce ferroptosis in allografts by restraining lipid peroxidation.
Insights
Tumor necrosis factor-α-induced protein-8 like 2 (TIPE2) deficiency reduces heart transplant rejection by inhibiting ferroptosis. This occurs through decreased T-cell interferon-γ (IFN-γ) production and restrained lipid peroxidation in allografts.
Area of Science:
- Immunology
- Cell Biology
- Transplantation Medicine
Background:
- Acute heart transplant rejection involves oxidative cell death.
- Ferroptosis, a form of oxidative cell death, has a poorly understood role in transplant rejection.
- Tumor necrosis factor-α-induced protein-8 like 2 (TIPE2) is crucial for immune homeostasis.
Purpose of the Study:
- To investigate the role of TIPE2 in mediating heart allograft rejection.
- To determine if TIPE2 influences ferroptosis in transplanted hearts.
- To elucidate the mechanisms by which TIPE2 affects immune responses in allografts.
Main Methods:
- Heart transplantation from BALB/c to C57BL/6 wild-type (WT) and TIPE2 knockout (TIPE2-/-) mice.
- Analysis of immune cell infiltration (CD3+, CD4+, CD8+) in allografts and lymphoid organs.
- Assessment of T-cell activation, interferon-γ (IFN-γ) production, and glutathione peroxidase 4 (GPX4) expression.
- In vitro experiments using myocardial cells treated with IFN-γ.
Main Results:
- TIPE2-/- recipient mice showed significantly reduced allograft injury and inhibited ferroptosis.
- Reduced infiltration and activation of CD4+ and CD8+ T cells were observed in TIPE2-/- mice.
- TIPE2 deficiency led to impaired IFN-γ production via the TBK1 pathway and increased GPX4 levels.
- IFN-γ treatment in vitro enhanced lipid peroxidation and decreased GPX4 expression by inhibiting MEK/ERK phosphorylation.
Conclusions:
- TIPE2 deficiency protects heart allografts by suppressing T-cell-mediated ferroptosis.
- The mechanism involves reduced IFN-γ production and subsequent restraint of lipid peroxidation.
- Targeting TIPE2 may offer a novel therapeutic strategy for preventing transplant rejection.
