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Converging TLR9 and PI3Kgamma signaling induces sterile inflammation and organ damage.
- Source :
-
Scientific reports [Sci Rep] 2019 Dec 13; Vol. 9 (1), pp. 19085. Date of Electronic Publication: 2019 Dec 13. - Publication Year :
- 2019
-
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.
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 2045-2322
- Volume :
- 9
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Scientific reports
- Publication Type :
- Academic Journal
- Accession number :
- 31836766
- Full Text :
- https://doi.org/10.1038/s41598-019-55504-0