YTHDF1 Identified As a Potential Therapeutic Target for Autoimmune Hepatitis
New Study Underscores The Pivotal Role Of YTHDF1 In Immune-Mediated Hepatitis
EINPresswire.com / -- Autoimmune hepatitis (AIH) is a severe autoimmune disease characterized by immune-mediated hepatocyte destruction, leading to hepatic necroinflammation, cirrhosis, and potential fatality. N6-methyladenosine (m6A), a prevalent post-transcriptional mRNA modification, dynamically regulates various cellular processes. However, the relationship between AIH and m6A and its regulators remains poorly understood.
This research, published in the Genes & Diseases journal by a team from Xiamen University, addresses the role of m6A and its regulators in T cell-mediated hepatitis.
In this study, the researchers utilized concanavalin A (ConA)-induced mouse liver damage as an experimental model for T cell-mediated hepatitis. Initial investigations revealed that the protein expression of m6A readers, YTHDF1, YTHDF2, and YTHDF3, during the early stage of ConA-induced hepatitis was dramatically decreased in the liver. Notably, YTHDF1-deficient (Ythdf1−/−) mice showed more susceptibility to ConA-induced liver injury, along with an intensified inflammatory storm accompanied by an aggravated hepatic inflammatory response via ERK and nuclear factor-kappa B (NF-κB) pathways.
This study not only highlights the crucial role of YTHDF1 in hematopoietic cells in suppressing T cell-mediated liver injury but also suggests an immunomodulatory and anti-inflammatory role for YTHDF1 in T cell-mediated hepatitis. Furthermore, Ythdf1−/− mice exhibited higher serum levels of proinflammatory cytokines upon ConA challenge, indicating that YTHDF1 deficiency sensitizes inflammatory cells to ConA, intensifying cytokine production and exacerbating hepatic inflammation. Interestingly, the activation of the NF-κB pathway and MAPKs signaling after ConA treatment in Ythdf1−/− mice further emphasizes the role of YTHDF1 in suppressing inflammatory responses.
Additionally, immunohistochemical staining results revealed significantly higher CD4+ cell numbers in the ConA-treated Ythdf1−/− mice livers than in wild type mice, implying that YTHDF1 deficiency could increase the infiltration and activation of inflammatory cells. Furthermore, this study demonstrates that YTHDF1 deletion in macrophages exacerbates lipopolysaccharide-induced inflammatory responses, emphasizing the necessity of YTHDF1 in immune cells for an effective inflammatory response.
In summary, this study uncovered that YTHDF1 deficiency exacerbates the immune response in ConA-induced hepatitis by modulating the expression of inflammatory mediators, highlighting the potential of YTHDF1 as a promising therapeutic target for clinical hepatitis.
Reference
Title of Original Paper: YTHDF1 shapes immune-mediated hepatitis via regulating inflammatory cell recruitment and response
Journal: Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch
DOI: https://doi.org/10.1016/j.gendis.2024.101327
Funding Information:
National Natural Science Foundation of China (No. 81772539, 81972238)
Fundamental Research Funds for the Central Universities of China-Xiamen University (No. 20720180048)
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Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis is placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases. The journal has worldwide authorship, and a broad scope in basic and translational biomedical research of molecular biology, molecular genetics, and cell biology, including but not limited to cell proliferation and apoptosis, signal transduction, stem cell biology, developmental biology, gene regulation and epigenetics, cancer biology, immunity and infection, neuroscience, disease-specific animal models, gene and cell-based therapies, and regenerative medicine.
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