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Published on: March 15, 2024
Macrophage Ferroptotic Resistance Is Required for the Progression of Infantile Hemangioma
Jingjing Liu1,2, Wenqun Zhong1,2, Rong Wang1
1State Key Laboratory of Oral and Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School and Hospital of Stomatology Wuhan University Wuhan China.
Background:
Ferroptosis is a programmed cell death caused by iron-dependent accumulation and cellular lipid peroxides, which is different from apoptosis and pyroptosis. This study investigated the possible effect of ferroptotic response in the pathogenesis of infantile hemangioma (IH).
Methods And Results:
The staining level of 4-hydroxynonenal (4-HNE), the marker of ferroptotic cells, was significantly increased in the involutive IH samples compared with the proliferative samples (9 proliferative versus 12 involutive lesions, P=0.0152). By contrast, the expression of glutathione peroxidase 4 (GPX4), a key enzyme regulating ferroptotic resistance, was significantly increased in the involutive IH samples. Meanwhile, the GPX4 was richly expressed in macrophages of IH. The data from in vitro study showed that the mRNA (P=0.0002) and protein (P=0.0385) expression levels of GPX4 were significantly upregulated in macrophages cultured with hemangioma-derived stem cells conditional medium (HemSC-CM). Mechanistically, HemSC-CM promoted the expression of GPX4 in macrophages (P=0.0482) by increasing nuclear factor erythroid 2-related factor 2 translocation to the nucleus (P=0.0026). Additionally, inhibition of GPX4 or inducing ferroptosis in macrophages could inhibit progression of lesion in IH nude mice mode.
Conclusions:
Hemangioma-derived stem cells (HemSCs) could promote macrophage ferroptotic resistance through upregulating expression of GPX4, which is required for the progression of IH.
Insights
Infantile hemangioma (IH) progression involves ferroptosis resistance. Hemangioma stem cells boost macrophage resistance by increasing glutathione peroxidase 4 (GPX4), a key factor in IH development.
Area of Science:
- Cell Biology
- Developmental Biology
- Pathology
Background:
- Ferroptosis is a distinct form of programmed cell death.
- This study explores ferroptosis's role in infantile hemangioma (IH) pathogenesis.
Purpose of the Study:
- Investigate the ferroptotic response in infantile hemangioma.
- Determine the role of ferroptosis in IH progression.
Main Methods:
- Analyzed 4-hydroxynonenal (4-HNE) and glutathione peroxidase 4 (GPX4) expression in IH lesions.
- Utilized in vitro macrophage cultures with hemangioma-derived stem cell conditional medium (HemSC-CM).
- Examined GPX4 regulation via nuclear factor erythroid 2-related factor 2 (Nrf2) pathway.
- Assessed ferroptosis inhibition effects in an IH mouse model.
Main Results:
- 4-HNE levels were higher in involutive IH compared to proliferative IH.
- GPX4 expression was significantly increased in involutive IH and in macrophages cultured with HemSC-CM.
- HemSC-CM upregulated GPX4 in macrophages by promoting Nrf2 nuclear translocation.
- Inhibiting GPX4 or inducing ferroptosis reduced IH lesion progression in mice.
Conclusions:
- Hemangioma-derived stem cells enhance macrophage ferroptosis resistance by upregulating GPX4.
- GPX4 upregulation is crucial for infantile hemangioma progression.
