Converging TLR9 and PI3Kgamma signaling induces sterile inflammation and organ damage

• Published in: Scientific reports Vol. 9; no. 1; pp. 19085 - 15
• Main Authors: Lima, Braulio Henrique Freire, Marques, Pedro Elias, Gomides, Lindisley Ferreira, Mattos, Matheus Silvério, Kraemer, Lucas, Queiroz-Junior, Celso M, Lennon, Mark, Hirsch, Emilio, Russo, Remo Castro, Menezes, Gustavo Batista, Hessel, Edith M, Amour, Augustin, Teixeira, Mauro Martins
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 13.12.2019; Nature Publishing Group UK
• Subjects: Animals; Cell Survival - drug effects; Class Ib Phosphatidylinositol 3-Kinase - metabolism; Cytokines - biosynthesis; Female; Gene Deletion; Inflammation; Inflammation - enzymology; Inflammation - pathology; Liver - drug effects; Liver - injuries; Liver - pathology; Lung - enzymology; Lung - pathology; Mice, Inbred C57BL; Oligodeoxyribonucleotides - pharmacology; Organ Specificity - drug effects; Pleura - metabolism; Pulmonary Fibrosis - chemically induced; Pulmonary Fibrosis - pathology; Quinoxalines - pharmacology; Signal Transduction - drug effects; Silicon Dioxide; Thiazolidinediones - pharmacology; TLR9 protein; Toll-Like Receptor 9 - metabolism; Toll-like receptors
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-55504-0

Toll-like receptor 9 (TLR9) and Phosphatidylinositol-3-kinase gamma (PI3Kγ) are very important effectors of the immune response, however, the importance of such crosstalk for disease development is still a matter of discussion. Here we show that PI3Kγ is required for immune responses in which TLR9 is a relevant trigger. We demonstrate the requirement of PI3Kγ for TLR9-induced inflammation in a model of CpG-induced pleurisy. Such requirement was further observed in inflammatory models where DNA sensing via TLR9 contributes to disease, such as silicosis and drug-induced liver injury. Using adoptive transfer, we demonstrate that PI3Kγ is important not only in leukocytes but also in parenchymal cells for the progression of inflammation. We demonstrate this crosstalk between TLR9 and PI3Kγ in vitro using human PBMCs. The inhibition of PI3Kγ in CpG-stimulated PBMCs resulted in reduction of both cytokine production and phosphorylated Akt. Therefore, drugs that target PI3Kγ have the potential to treat diseases mediated by excessive TLR9 signalling.