Kidney Week

Abstract: FR-PO844

Global Lactylome Reveals Lactylation-Dependent Mechanisms Underlying Th17 Differentiation in Lupus Nephritis

Session Information

• Glomerular Diseases: Inflammation and Immunology
  October 25, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Glomerular Diseases

• 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology

Author

• Zhang, Mingyang, Army Medical University, ChongQing, ChongQing, China

Mingyang Zhang

Background

The dysregulation of CD4⁺T cell differentiation is closely related to the occurrence and development of lupus nephritis, Metabolic reprogramming from oxidative phosphorylation to glycolysis and accumulation of lactate are involved in this process. lactate-derived lactylation regulated the aberrant activation and differentiation of T cells.However, the underlying mechanisms remain unclear.

Methods

Western blot and immunofluorescence were used to show the changes of lactylation level of CD4⁺T cells in MRL/Lpr mice at different stages of disease. The impact of reducing and increasing lactylation by intraperitoneal administered of the pyruvate dehydrogenase kinase dichloroacetate (DCA) and rotenone, aiming to assess their disease progression of lupus nephritis (LN). Global lactylome reveals important differential lactylation modification sites, and ChIP-seq was used to analyze the key downstream genes regulated by lactylation modification sites, thus influencing the differentiation process of CD4⁺ T cells.

Results

we find that lactate-derived lactylation regulated CD4⁺T cell differentiation. Lactylation levels in CD4⁺T cells increased with the progression of lupus nephritis (LN). Inhibition of lactylation suppressed TH17 differentiation and attenuated LN inflammation. The global lactylome revealed the landscape of lactylated sites and proteins in the CD4⁺T cells of normal and MRL/Lpr mice. Specifically, hyperlactylation of Ikzf1 at Lys³⁷³ promoted Th17 differentiation by directly modulating the expression of Th17-related genes. However,Delactylation of Ikzf1 at Lys³⁷³ impaired TH17 differentiation.

Conclusion

Ikzf1 Lactylation is involved in the pathogenesis of lupus nephritis by specifically promoting Th17 differentiation，It may become a potential therapeutic target for delaying the progression of lupus nephritis.

Funding

• Clinical Revenue Support