A research team led by Professor Hsieh Zhongyu from Sun Yat-sen University has uncovered a new mechanism by which Pim1 controls Th17 cell differentiation through mitochondrial metabolism. Through a molecular docking screen, they identified nilotinib as a potential drug candidate for the treatment of inflammatory arthritis by targeting Pim1. The related results are: the study (DOI: 10.34133/research.1137), titled “Pim1 functions as a therapeutic target for inflammatory arthritis via mitochondrial metabolism and Th17 cell differentiation.”
Research background
Inflammatory arthritis, which primarily includes rheumatoid arthritis and ankylosing spondylitis, is a chronic and progressive bone-immune-related disease characterized by bone destruction in the joints, seriously threatening the health and quality of life of patients. The core pathological mechanism of inflammatory arthritis is closely related to abnormal Th17 cell differentiation. Th17 cells secrete pathogenic cytokines, such as IL-17A and IL-17F, and recruit other inflammatory cells to modulate their function, thereby mediating cartilage erosion and bone destruction. Elucidating the mechanism of aberrant Th17 cell differentiation in inflammatory arthritis will help to better understand its pathogenesis and explore new therapeutic options.
Pim1 is a serine/threonine protein kinase that participates in the development and development of bone immune-related diseases by mediating cytokine-dependent signaling in T cells. Previous studies have reported that Pim1 can influence the differentiation potential of T cells, but its pathogenic role and specific mechanism in inflammatory arthritis, as well as whether specific targeting of Pim1 has therapeutic potential for osteoimmune-related diseases, remain unclear.
Research progress
Elevated expression of Pim1 is the main cause of abnormal Th17 cell differentiation in inflammatory arthritis
The research team found that Pim1 protein levels were significantly upregulated in CD4+ T cells in the peripheral blood and inflamed joints of patients with rheumatoid arthritis (RA) and ankylosing spondylitis (AS), and this was closely associated with an increased proportion of Th17 cells. By constructing mice with a specific knockout of Pim1 in CD4⁺ T cells (Pim1 cKO), the research team found that Pim1 cKO mice had significantly reduced symptoms of inflammatory arthritis, such as joint swelling, inflammatory infiltrates, cartilage destruction, and bone erosion, as well as a marked reduction in the proportion of Th17 cells and a significant reduction in IL-17A expression (Figure 1).
Pim1 promotes Th17 cell differentiation by regulating mitochondrial metabolism
Further investigation by the research team showed that Pim1 promotes mitochondrial calcium influx by phosphorylating mitochondrial calcium uptake protein 1 (MICU1), thereby activating mitochondrial oxidative phosphorylation and providing energy and metabolic support for Th17 cell differentiation. In vitro experiments confirmed that elevated expression of Pim1 significantly promoted Th17 cell differentiation and Th17 cell-associated virulence gene expression, and these effects were blocked by mitochondrial calcium influx inhibitors (Figure 2).
Nilotinib, which targets Pim1, can significantly inhibit Th17 cell differentiation and alleviate inflammatory arthritis.
The research team used molecular docking and dynamic simulation techniques to screen nilotinib from an FDA-approved drug library as a specific inhibitor of Pim1. This drug stably binds to the active pocket of Pim1, inhibits its kinase activity, and suppresses Th17 cell differentiation. In vivo experiments showed that nilotinib could significantly inhibit Th17 cell differentiation and reduce joint swelling, inflammatory infiltration, cartilage destruction, and bone erosion in mice, while these effects were blocked in Pim1 cKO mice (Figure 3).
Future prospects
Further optimization of the dosing regimen and improved evaluation of the safety and efficacy of nilotinib are expected to facilitate the translational application of nilotinib in the clinical treatment of inflammatory arthritis. Meanwhile, the development of delivery systems for Pim1 inhibitors that specifically target CD4⁺ T cells is expected to further improve their therapeutic specificity and expand treatment options for inflammatory arthritis and other Th17 cell-related autoimmune diseases.
sauce:
Science and Technology Review Publishing
Reference magazines:
DOI: 10.34133/research.1137. https://spj.science.org/doi/10.34133/research.1137
