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Here we show that PI3K\u03b3 is required for immune responses in which TLR9 is a relevant trigger. We demonstrate the requirement of PI3K\u03b3 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 PI3K\u03b3 is important not only in leukocytes but also in parenchymal cells for the progression of inflammation. We demonstrate this crosstalk between TLR9 and PI3K\u03b3 <jats:italic>in vitro<\/jats:italic> using human PBMCs. The inhibition of PI3K\u03b3 in CpG-stimulated PBMCs resulted in reduction of both cytokine production and phosphorylated Akt. Therefore, drugs that target PI3K\u03b3 have the potential to treat diseases mediated by excessive TLR9 signalling.<\/jats:p>","DOI":"10.1038\/s41598-019-55504-0","type":"journal-article","created":{"date-parts":[[2019,12,13]],"date-time":"2019-12-13T11:04:00Z","timestamp":1576235040000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Converging TLR9 and PI3Kgamma signaling induces sterile inflammation and organ damage"],"prefix":"10.1038","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1226-1665","authenticated-orcid":false,"given":"Braulio Henrique Freire","family":"Lima","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5613-8012","authenticated-orcid":false,"given":"Pedro Elias","family":"Marques","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lindisley Ferreira","family":"Gomides","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9163-6279","authenticated-orcid":false,"given":"Matheus Silv\u00e9rio","family":"Mattos","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lucas","family":"Kraemer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7884-7709","authenticated-orcid":false,"given":"Celso M.","family":"Queiroz-Junior","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark","family":"Lennon","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9073-6024","authenticated-orcid":false,"given":"Emilio","family":"Hirsch","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1715-3834","authenticated-orcid":false,"given":"Remo Castro","family":"Russo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gustavo Batista","family":"Menezes","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2339-4482","authenticated-orcid":false,"given":"Edith M.","family":"Hessel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7369-415X","authenticated-orcid":false,"given":"Augustin","family":"Amour","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6944-3008","authenticated-orcid":false,"given":"Mauro Martins","family":"Teixeira","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2019,12,13]]},"reference":[{"key":"55504_CR1","doi-asserted-by":"publisher","first-page":"740","DOI":"10.1038\/35047123","volume":"408","author":"H Hemmi","year":"2000","unstructured":"Hemmi, H. et al. 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