1. Converging TLR9 and PI3Kgamma signaling induces sterile inflammation and organ damage.
- Author
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Lima BHF, Marques PE, Gomides LF, Mattos MS, Kraemer L, Queiroz-Junior CM, Lennon M, Hirsch E, Russo RC, Menezes GB, Hessel EM, Amour A, and Teixeira MM
- Subjects
- Animals, Cell Survival drug effects, Cytokines biosynthesis, Female, Gene Deletion, Inflammation enzymology, Liver drug effects, Liver injuries, Liver pathology, Lung enzymology, Lung pathology, Mice, Inbred C57BL, Oligodeoxyribonucleotides pharmacology, Pleura metabolism, Pulmonary Fibrosis chemically induced, Pulmonary Fibrosis pathology, Quinoxalines pharmacology, Silicon Dioxide, Thiazolidinediones pharmacology, Class Ib Phosphatidylinositol 3-Kinase metabolism, Inflammation pathology, Organ Specificity drug effects, Signal Transduction drug effects, Toll-Like Receptor 9 metabolism
- Abstract
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.
- Published
- 2019
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