The phosphoinositide-3-kinase (PI3K)-delta inhibitor seletalisib impairs monocyte-derived dendritic cells maturation, APC function, and promotes their migration to CCR7 and CXCR4 ligands. Issue 3 (24th February 2022)

• Record Type: Journal Article
• Authors: Scopelliti, Fernanda; Mercurio, Laura; Cattani, Caterina; Dimartino, Valentina; Albanesi, Cristina; Costanzo, Gianfranco; Mirisola, Concetta; Madonna, Stefania; Cavani, Andrea
• Is Part Of: Journal of leukocyte biology. Volume 112:Issue 3(2022)
• Page Start: 383
• Page End: 393
• Publication Date: 2022-02-24
• Subjects: dendritic cells -- PI3K p110δ -- seletalisib -- CCR7 -- CXCR4; Leucocytes -- Periodicals; Reticulo-endothelial system -- Periodicals; 571.96
• DOI: 10.1002/JLB.1A0821-413RR
• Languages: English
• ISSNs: 0741-5400

Abstract

Abstract: PI3K pathway plays a crucial role in dendritic cells (DCs) functions, as it regulates different cellular processes, such as maturation and cytokines production. However, the specific role of PI3K p110δ isoform in human DCs has not been thoroughly addressed. In this study, we analyze the effects of seletalisib, a potent and specific inhibitor of PI3K p110δ, on phenotype and antigen-presenting functions of monocyte-derived DCs undergone maturation via LPS. Seletalisib treatment reduced membrane HLA-DR as well as CD83 and CD40 costimulatory molecules, whereas CD80 and CD86 expression was only partially affected. Additionally, DCs cultures showed reduced TNF-α, IL-10, and IL-12 and increased IL-23 secretion levels. This resulted in a reduced capacity of DCs to prime allogeneic T cells, with a strong decrease of Th1 differentiation. On the other hand, PI3K p110δ inhibitor seletalisib increased CXCR4 and CCR7 expression and augmented the DCs migration toward CCL19 and CXCL12 ligands. At molecular level, inhibition of PI3K p110δ isoform by seletalisib significantly down-regulated the phosphorylation of AKT and other downstream signaling molecules, such as ribosomal protein S6, 4E-BP1, and NF-κB p65. In contrast, seletalisib did not affect p38 MAP kinase phosphorylation or TLR-associated adapter molecule TIRAP in DCs. Our results indicate that PI3K p110δ can serve as an important regulatory signal for DCs, and selective inhibition of PI3K p110δ isoform by seletalisib could be used for the prevention of exaggerated and harmful immune responses occurring in pathologic conditions, such as autoimmune disorders. Graphical Abstract: The study demonstrate that the PI3K-δ inhibitor Seletalisib impairs maturation of DCs while increasing expression of chemokine receptor involved in DC migration toward lymph nodes