G1 and G2 ApolipoproteinL1 modulate macrophage inflammation and lipid accumulation through the polyamine pathway
Year: 2025
Type: preprint
Abstract: The G1 and G2 variants of the gene encoding Apolipoprotein L1 ( APOL1 ) increase risk for kidney disease and cardiometabolic traits. While previous studies have elucidated key mechanisms by which G1 and G2 APOL1 cause cellular inflammation and cytotoxicity, it remains unclear whether these mechanisms drive inflammation in G1 and G2 macrophages. In this study, we used mouse bone-marrow-derived macrophages and human induced pluripotent stem cell-derived macrophages to identify altered immune signaling and inflammatory activation caused by G1 and G2 APOL1 . We demonstrated that G1 and G2 APOL1 increased lipid accumulation, pro-inflammatory cytokine expression, and inflammasome signaling; this inflammatory response was sustained when treated with anti-inflammatory cytokines IL-4 and IL-10. Additionally, in G1 and G2 macrophages we observed increased mitochondrial size and elongation, oxidative phosphorylation, and glycolysis. Finally, we used unbiased metabolite analysis to identify an accumulation of polyamine spermidine and the enrichment of the spermidine synthesis pathway in G1 and G2 macrophages. When treated with polyamine inhibitor α-difluoromethylornithine (DFMO), lipid accumulation and inflammasome gene expression decreased in G1 and G2 macrophages. Together, these findings establish the pro-inflammatory effects of G1 and G2 APOL1 in macrophages and identify a novel pathway which ameliorates G1 and G2 effects on cellular inflammation.
Authors: Esther Liu, Matthew Wright, Andrew O. Kearney, Tiffany Caza, Johnson Y. Yang, Valerie Garcia, Amal O. Dadi, Shuta Ishibe, Navdeep S. Chandel, Hanrui Zhang, Edward B. Thorp, Jennie Lin
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Awards: G1164661550, G1284175734, G1382277591, G1697802790, G23745306, G317886719, G4001230836, G4159268500, G4372147948, G6544658276, G9000046704, G9000243582, G9000243610, NRSA Training Core, Macrophages and attenuation of inflammation resolution in APOL1 nephropathy, The Robert H. Lurie Comprehensive Cancer Center, Uncovering Mechanisms of Risk-Variant APOL1-modulated Inflammatory Signaling in Macrophages, Phagocyte Crosstalk in the Balance of Inflammation & Cardiac Disease, Chicago Kidney Urology Hematology network FOR city-Wide reseArch tRaining and career Development (Chicago KUH FORWARD), Integrated epidemiology of systemic and plaque-specific immunologic features of human atherosclerosis
OpenAlex ID: W4411133147