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Author Spotlight: Achieving High-Purity In Vitro Differentiation of Th17 Cells Using Cytokine Concentration Modulation
Published on: October 25, 2024
PCSK9 inhibition ameliorates experimental autoimmune myocarditis by reducing Th17 cell differentiation through
Miao Yu1, Wenjing Tang1, Wei Liang1
1Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China; Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China; Hubei Provincial Engineering Research Center of Immunological Diagnosis and Therapy for Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
Abstract:
Proprotein convertase subtilisin kexin type 9 (PCSK9) was characterized as a protein regulating circulating cholesterol metabolism; however, recent studies demonstrated a role for PCSK9 in inflammatory and autoimmune diseases unrelated to cholesterol alterations. The implication of PCSK9 in myocarditis is unclear and we aim at investigating the roles and mechanisms of PCSK9 in myocarditis. Male BALB/c mice received subcutaneous immunization with MyHC-α peptide on days 0 and 7 to establish the experimental autoimmune myocarditis (EAM) model. PCSK9 inhibitor, evolocumab, was administered subcutaneously once a week starting on day 0 and all mice were euthanized on day 21. Our results showed that PCSK9 inhibition ameliorated the cardiac inflammation of EAM mice. PCSK9 inhibition reduced both the levels of cardiac and peripheral blood PCSK9. We found that CD4+ T cells, CD8+ T cells, macrophages, and cardiomyocytes in the heart of EAM mice could express PCSK9. PCSK9 inhibition decreased the differentiation of cardiac Th17 cells by lowering ROR-γt levels but had no effects on Th1, Th2, and Treg cell differentiation. In vitro experiments of CD4+ T cells, we found that PCSK9 directly promoted Th17 cell differentiation through LDLR/STAT3/ROR-γt pathway. Collectively, we demonstrated that PCSK9 inhibition ameliorated the severity of EAM mice by reducing Th17 cell differentiation. PCSK9 is a promising target for treating myocarditis.
Insights
Proprotein convertase subtilisin kexin type 9 (PCSK9) inhibition reduced cardiac inflammation in experimental autoimmune myocarditis. PCSK9 blockade decreased Th17 cell differentiation, suggesting PCSK9 as a therapeutic target for myocarditis.
Area of Science:
- Immunology
- Cardiovascular Research
- Molecular Biology
Background:
- Proprotein convertase subtilisin kexin type 9 (PCSK9) is known for cholesterol regulation.
- Emerging evidence links PCSK9 to inflammatory and autoimmune conditions beyond lipid metabolism.
- The role of PCSK9 in myocarditis remains largely unexplored.
Purpose of the Study:
- To investigate the role and underlying mechanisms of PCSK9 in experimental autoimmune myocarditis (EAM).
- To evaluate the therapeutic potential of PCSK9 inhibition in ameliorating myocarditis.
Main Methods:
- Established an EAM mouse model using MyHC-α peptide immunization.
- Administered PCSK9 inhibitor (evolocumab) to EAM mice.
- Assessed cardiac inflammation, PCSK9 levels, immune cell populations (CD4+, CD8+ T cells, macrophages), and cardiomyocyte involvement.
- Conducted in vitro studies on CD4+ T cells to elucidate PCSK9's mechanism on Th17 differentiation via the LDLR/STAT3/ROR-γt pathway.
Main Results:
- PCSK9 inhibition significantly reduced cardiac inflammation in EAM mice.
- Reduced levels of both cardiac and peripheral blood PCSK9 were observed following inhibition.
- PCSK9 was expressed in cardiac CD4+ T cells, CD8+ T cells, macrophages, and cardiomyocytes.
- PCSK9 inhibition specifically decreased Th17 cell differentiation by downregulating ROR-γt, without affecting Th1, Th2, or Treg cells.
- In vitro, PCSK9 was shown to directly promote Th17 cell differentiation.
Conclusions:
- PCSK9 inhibition ameliorates experimental autoimmune myocarditis severity.
- The therapeutic effect is mediated by the reduction of Th17 cell differentiation through the LDLR/STAT3/ROR-γt pathway.
- PCSK9 represents a promising therapeutic target for the treatment of myocarditis.
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