Discovery - University of Dundee - Online Publications

Library & Learning Centre

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

Standard

Phosphorylation of CRTC3 by the salt-inducible kinases controls the interconversion of classically activated and regulatory macrophages. / Clark, Kristopher; Mackenzie, Kirsty F; Petkevicius, Kasparas; Kristariyanto, Yosua; Zhang, Jiazhen; Choi, Hwan Geun; Peggie, Mark; Plater, Lorna; Pedrioli, Patrick G A; McIver, Ed; Gray, Nathanael S; Arthur, J Simon C; Cohen, Philip (Lead / Corresponding author).

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 109, No. 42, 2012, p. 16986-91.

Research output: Contribution to journalArticle

Harvard

Clark, K, Mackenzie, KF, Petkevicius, K, Kristariyanto, Y, Zhang, J, Choi, HG, Peggie, M, Plater, L, Pedrioli, PGA, McIver, E, Gray, NS, Arthur, JSC & Cohen, P 2012, 'Phosphorylation of CRTC3 by the salt-inducible kinases controls the interconversion of classically activated and regulatory macrophages' Proceedings of the National Academy of Sciences of the United States of America, vol 109, no. 42, pp. 16986-91., 10.1073/pnas.1215450109

APA

Clark, K., Mackenzie, K. F., Petkevicius, K., Kristariyanto, Y., Zhang, J., Choi, H. G., ... Cohen, P. (2012). Phosphorylation of CRTC3 by the salt-inducible kinases controls the interconversion of classically activated and regulatory macrophages. Proceedings of the National Academy of Sciences of the United States of America, 109(42), 16986-91. 10.1073/pnas.1215450109

Vancouver

Clark K, Mackenzie KF, Petkevicius K, Kristariyanto Y, Zhang J, Choi HG et al. Phosphorylation of CRTC3 by the salt-inducible kinases controls the interconversion of classically activated and regulatory macrophages. Proceedings of the National Academy of Sciences of the United States of America. 2012;109(42):16986-91. Available from: 10.1073/pnas.1215450109

Author

Clark, Kristopher; Mackenzie, Kirsty F; Petkevicius, Kasparas; Kristariyanto, Yosua; Zhang, Jiazhen; Choi, Hwan Geun; Peggie, Mark; Plater, Lorna; Pedrioli, Patrick G A; McIver, Ed; Gray, Nathanael S; Arthur, J Simon C; Cohen, Philip (Lead / Corresponding author) / Phosphorylation of CRTC3 by the salt-inducible kinases controls the interconversion of classically activated and regulatory macrophages.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 109, No. 42, 2012, p. 16986-91.

Research output: Contribution to journalArticle

Bibtex - Download

@article{13bec612a8a647d69694b96996561e45,
title = "Phosphorylation of CRTC3 by the salt-inducible kinases controls the interconversion of classically activated and regulatory macrophages",
author = "Kristopher Clark and Mackenzie, {Kirsty F} and Kasparas Petkevicius and Yosua Kristariyanto and Jiazhen Zhang and Choi, {Hwan Geun} and Mark Peggie and Lorna Plater and Pedrioli, {Patrick G A} and Ed McIver and Gray, {Nathanael S} and Arthur, {J Simon C} and Philip Cohen",
year = "2012",
doi = "10.1073/pnas.1215450109",
volume = "109",
number = "42",
pages = "16986--91",
journal = "Proceedings of the National Academy of Sciences of the United States of America",

}

RIS (suitable for import to EndNote) - Download

TY - JOUR

T1 - Phosphorylation of CRTC3 by the salt-inducible kinases controls the interconversion of classically activated and regulatory macrophages

A1 - Clark,Kristopher

A1 - Mackenzie,Kirsty F

A1 - Petkevicius,Kasparas

A1 - Kristariyanto,Yosua

A1 - Zhang,Jiazhen

A1 - Choi,Hwan Geun

A1 - Peggie,Mark

A1 - Plater,Lorna

A1 - Pedrioli,Patrick G A

A1 - McIver,Ed

A1 - Gray,Nathanael S

A1 - Arthur,J Simon C

A1 - Cohen,Philip

AU - Clark,Kristopher

AU - Mackenzie,Kirsty F

AU - Petkevicius,Kasparas

AU - Kristariyanto,Yosua

AU - Zhang,Jiazhen

AU - Choi,Hwan Geun

AU - Peggie,Mark

AU - Plater,Lorna

AU - Pedrioli,Patrick G A

AU - McIver,Ed

AU - Gray,Nathanael S

AU - Arthur,J Simon C

AU - Cohen,Philip

PY - 2012

Y1 - 2012

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84867650065&partnerID=8YFLogxK

U2 - 10.1073/pnas.1215450109

DO - 10.1073/pnas.1215450109

M1 - Article

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 42

VL - 109

SP - 16986

EP - 16991

ER -

Documents

Library & Learning Centre

Contact | Accessibility | Policy