title: Phosphorylation of CRTC3 by the salt-inducible kinases controls the interconversion of classically activated and regulatory macrophages.
abstract: Macrophages acquire strikingly different properties that enable them to play key roles during the initiation, propagation, and resolution of inflammation. Classically activated (M1) macrophages produce proinflammatory mediators to combat invading pathogens and respond to tissue damage in the host, whereas regulatory macrophages (M2b) produce high levels of anti-inflammatory molecules, such as IL-10, and low levels of proinflammatory cytokines, like IL-12, and are important for the resolution of inflammatory responses. A central problem in this area is to understand how the formation of regulatory macrophages can be promoted at sites of inflammation to prevent and/or alleviate chronic inflammatory and autoimmune diseases. Here, we demonstrate that the salt-inducible kinases (SIKs) restrict the formation of regulatory macrophages and that their inhibition induces striking increases in many of the characteristic markers of regulatory macrophages, greatly stimulating the production of IL-10 and other anti-inflammatory molecules. We show that SIK inhibitors elevate IL-10 production by inducing the dephosphorylation of cAMP response element-binding protein (CREB)-regulated transcriptional coactivator (CRTC) 3, its dissociation from 14-3-3 proteins and its translocation to the nucleus where it enhances a gene transcription program controlled by CREB. Importantly, the effects of SIK inhibitors on IL-10 production are lost in macrophages that express a drug-resistant mutant of SIK2. These findings identify SIKs as a key molecular switch whose inhibition reprograms macrophages to an anti-inflammatory phenotype. The remarkable effects of SIK inhibitors on macrophage function suggest that drugs that target these protein kinases may have therapeutic potential for the treatment of inflammatory and autoimmune diseases.
authors.affiliation: Medical Research Council Protein Phosphorylation Unit, College of Life Sciences, Sir James Black Centre, University of Dundee, Dundee, DD1 5EH, United Kingdom.
authors.forename: Kristopher
authors.initials: K
authors.lastname: Clark
authors.forename: Kirsty F
authors.initials: KF
authors.lastname: MacKenzie
authors.forename: Kasparas
authors.initials: K
authors.lastname: Petkevicius
authors.forename: Yosua
authors.initials: Y
authors.lastname: Kristariyanto
authors.forename: Jiazhen
authors.initials: J
authors.lastname: Zhang
authors.forename: Hwan Geun
authors.initials: HG
authors.lastname: Choi
authors.forename: Mark
authors.initials: M
authors.lastname: Peggie
authors.forename: Lorna
authors.initials: L
authors.lastname: Plater
authors.forename: Patrick G A
authors.initials: PG
authors.lastname: Pedrioli
authors.forename: Ed
authors.initials: E
authors.lastname: McIver
authors.forename: Nathanael S
authors.initials: NS
authors.lastname: Gray
authors.forename: J Simon C
authors.initials: JS
authors.lastname: Arthur
authors.forename: Philip
authors.initials: P
authors.lastname: Cohen
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D002460:Cell Line; D003503:Cyclobutanes / Q000138:chemical synthesis / Q000494:pharmacology*; D016207:Cytokines / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D018076:DNA, Complementary / Q000235:genetics; D005455:Fluorescent Antibody Technique; D015151:Immunoblotting; D007189:Indans / Q000494:pharmacology*; D007249:Inflammation / Q000276:immunology*; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D018345:Mice, Knockout; D015394:Molecular Structure; D009025:Morpholines / Q000138:chemical synthesis / Q000494:pharmacology*; D010671:Phenylurea Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D040901:Proteomics; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D034622:RNA Interference; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: C555318:CRTC3 protein, mouse; D003503:Cyclobutanes; D016207:Cytokines; D017931:DNA Primers; D018076:DNA, Complementary; C577044:HG-9-91-01; D007189:Indans; C577045:MRT199665; C556458:MRT67307; D009025:Morpholines; D010671:Phenylurea Compounds; D011743:Pyrimidines; D014157:Transcription Factors; D016753:Interleukin-10; C474808:salt-inducible kinase-2, mouse; D017346:Protein Serine-Threonine Kinases