title: The clinically approved drugs dasatinib and bosutinib induce anti-inflammatory macrophages by inhibiting the salt-inducible kinases.
abstract: Macrophages switch to an anti-inflammatory, 'regulatory'-like phenotype characterized by the production of high levels of interleukin (IL)-10 and low levels of pro-inflammatory cytokines to promote the resolution of inflammation. A potential therapeutic strategy for the treatment of chronic inflammatory diseases would be to administer drugs that could induce the formation of 'regulatory'-like macrophages at sites of inflammation. In the present study, we demonstrate that the clinically approved cancer drugs bosutinib and dasatinib induce several hallmark features of 'regulatory'-like macrophages. Treatment of macrophages with bosutinib or dasatinib elevates the production of IL-10 while suppressing the production of IL-6, IL-12p40 and tumour necrosis factor α (TNFα) in response to Toll-like receptor (TLR) stimulation. Moreover, macrophages treated with bosutinib or dasatinib express higher levels of markers of 'regulatory'-like macrophages including LIGHT, SPHK1 and arginase 1. Bosutinib and dasatinib were originally developed as inhibitors of the protein tyrosine kinases Bcr-Abl and Src but we show that, surprisingly, the effects of bosutinib and dasatinib on macrophage polarization are the result of the inhibition of the salt-inducible kinases. Consistent with the present finding, bosutinib and dasatinib induce the dephosphorylation of CREB-regulated transcription co-activator 3 (CRTC3) and its nuclear translocation where it induces a cAMP-response-element-binding protein (CREB)-dependent gene transcription programme including that of IL-10. Importantly, these effects of bosutinib and dasatinib on IL-10 gene expression are lost in macrophages expressing a drug-resistant mutant of salt-inducible kinase 2 (SIK2). In conclusion, our study identifies the salt-inducible kinases as major targets of bosutinib and dasatinib that mediate the effects of these drugs on the innate immune system and provides novel mechanistic insights into the anti-inflammatory properties of these drugs.
authors.affiliation: *MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, Sir James Black Centre, University of Dundee, Dundee DD1 5EH, Scotland, U.K.
authors.forename: James
authors.initials: J
authors.lastname: Ozanne
authors.affiliation: †Cell Signaling and Immunology, College of Life Sciences, Sir James Black Centre, University of Dundee, Dundee DD1 5EH, Scotland, U.K.
authors.forename: Alan R
authors.initials: AR
authors.lastname: Prescott
authors.affiliation: *MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, Sir James Black Centre, University of Dundee, Dundee DD1 5EH, Scotland, U.K.
authors.forename: Kristopher
authors.initials: K
authors.lastname: Clark
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology*; D000818:Animals; D001119:Arginase / Q000276:immunology; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000276:immunology; D016207:Cytokines / Q000276:immunology; D000069439:Dasatinib; D007113:Immunity, Innate / Q000187:drug effects*; D008264:Macrophages / Q000166:cytology / Q000276:immunology*; D051379:Mice; D009570:Nitriles / Q000494:pharmacology*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000276:immunology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000276:immunology; D011743:Pyrimidines / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology*; D014157:Transcription Factors / Q000276:immunology; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14 / Q000276:immunology; D000099157:Sphingosine Kinase
chemical_list: D000814:Aniline Compounds; D001119:Arginase; D017362:Cyclic AMP Response Element-Binding Protein; D016207:Cytokines; D000069439:Dasatinib; D009570:Nitriles; D017853:Phosphotransferases (Alcohol Group Acceptor); D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011743:Pyrimidines; D011804:Quinolines; D013844:Thiazoles; D014157:Transcription Factors; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14; D000099157:Sphingosine Kinase; C555318:CRTC3 protein, mouse; C492004:Creb1 protein, mouse; C505915:Tnfsf14 protein, mouse; C471992:bosutinib; C474808:salt-inducible kinase-2, mouse; C544448:Arg1 protein, mouse