Phosphorylation of CRTC3 by the salt-inducible kinases controls the interconversion of classically activated and regulatory macrophages

Kristopher Clark, Kirsty F Mackenzie, Kasparas Petkevicius, Yosua Kristariyanto, Jiazhen Zhang, Hwan Geun Choi, Mark Peggie, Lorna Plater, Patrick G A Pedrioli, Ed McIver, Nathanael S Gray, J Simon C Arthur, Philip Cohen (Lead / Corresponding author)

    Research output: Contribution to journalArticle

    117 Citations (Scopus)

    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.
    Original languageEnglish
    Pages (from-to)16986-91
    Number of pages6
    JournalProceedings of the National Academy of Sciences of the United States of America
    Volume109
    Issue number42
    DOIs
    Publication statusPublished - 2012

    Fingerprint Dive into the research topics of 'Phosphorylation of CRTC3 by the salt-inducible kinases controls the interconversion of classically activated and regulatory macrophages'. Together they form a unique fingerprint.

  • Press / Media

    Research reveals how immune cells can be altered to help fight inflammatory diseases

    Kristopher Clark, Kirsty MacKenzie, Mark Peggie, Lorna Plater, Patrick G. A. Pedrioli, J. Simon C. Arthur & Philip Cohen

    11/10/12

    1 item of Media coverage

    Press/Media: Research

    Cite this