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.
Highlights
Drug development for the treatment of chronic inflammatory diseases has mainly focused on interfering with the proinflammatory pathways driving the acute inflammatory response
Bosutinib and dasatinib were originally developed as drugs to block the activity of the protein tyrosine kinase Bcr-Abl, which is responsible for most cases of chronic myeloid leukaemia
Our data clearly show that the effects of these drugs on macrophage polarization are mediated by the salt-inducible kinases (SIK)
Summary
Drug development for the treatment of chronic inflammatory diseases has mainly focused on interfering with the proinflammatory pathways driving the acute inflammatory response. One group of antiinflammatory macrophages is the ‘regulatory’-like macrophages induced by cAMP-elevating agonists such as prostaglandin E2 (PGE2), immune complexes, glucocorticoids and interleukin (IL)-10 [4] This macrophage population may have potent immunomodulatory functions as it produces large quantities of the anti-inflammatory cytokine IL-10 while producing very low levels of pro-inflammatory mediators such as tumour necrosis factor α (TNFα) and IL-12 in response to activation of Toll-like receptors (TLRs) [4]. This macrophage population expresses a number of specific markers including SPHK1 and LIGHT [5], which distinguishes them from ‘alternatively activated’ macrophages induced by IL-4 which express FIZZ and YM1 [6]. A potential therapeutic strategy for the treatment of chronic inflammatory and autoimmune diseases could involve the administration of compounds inducing the formation of ‘regulatory’-like macrophages to promote the resolution of inflammation
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
