Granulocyte macrophage colony-stimulating factor induces CCL17 production via IRF4 to mediate inflammation

Adrian Achuthan, Andrew D. Cook, Ming Chin Lee, Reem Saleh, Hsu Wei Khiew, Melody W.N. Chang, Cynthia Louis, Andrew J Fleetwood, Derek C. Lacey, Anne D. Christensen, Ashlee T. Frye, Pui Yeng Lam, Hitoshi Kusano, Koji Nomura, Nancy Steiner, Irmgard Förster, Stephen L Nutt, Moshe Olshansky, Stephen J. Turner, John A. Hamilton

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Data from preclinical and clinical studies have demonstrated that granulocyte macrophage colony-stimulating factor (GMCSF) can function as a key proinflammatory cytokine. However, therapies that directly target GM-CSF function could lead to undesirable side effects, creating a need to delineate downstream pathways and mediators. In this work, we provide evidence that GM-CSF drives CCL17 production by acting through an IFN regulatory factor 4-dependent (IRF4-dependent) pathway in human monocytes, murine macrophages, and mice in vivo. In murine models of arthritis and pain, IRF4 regulated the formation of CCL17, which mediated the proinflammatory and algesic actions of GM-CSF. Mechanistically, GM-CSF upregulated IRF4 expression by enhancing JMJD3 demethylase activity. We also determined that CCL17 has chemokineindependent functions in inflammatory arthritis and pain. These findings indicate that GM-CSF can mediate inflammation and pain by regulating IRF4-induced CCL17 production, providing insights into a pathway with potential therapeutic avenues for the treatment of inflammatory diseases and their associated pain.

Original languageEnglish
Pages (from-to)3453-3466
Number of pages14
JournalJournal of Clinical Investigation
Volume126
Issue number9
DOIs
Publication statusPublished - 1 Sep 2016
Externally publishedYes

Cite this

Achuthan, A., Cook, A. D., Lee, M. C., Saleh, R., Khiew, H. W., Chang, M. W. N., ... Hamilton, J. A. (2016). Granulocyte macrophage colony-stimulating factor induces CCL17 production via IRF4 to mediate inflammation. Journal of Clinical Investigation, 126(9), 3453-3466. https://doi.org/10.1172/JCI87828
Achuthan, Adrian ; Cook, Andrew D. ; Lee, Ming Chin ; Saleh, Reem ; Khiew, Hsu Wei ; Chang, Melody W.N. ; Louis, Cynthia ; Fleetwood, Andrew J ; Lacey, Derek C. ; Christensen, Anne D. ; Frye, Ashlee T. ; Lam, Pui Yeng ; Kusano, Hitoshi ; Nomura, Koji ; Steiner, Nancy ; Förster, Irmgard ; Nutt, Stephen L ; Olshansky, Moshe ; Turner, Stephen J. ; Hamilton, John A. / Granulocyte macrophage colony-stimulating factor induces CCL17 production via IRF4 to mediate inflammation. In: Journal of Clinical Investigation. 2016 ; Vol. 126, No. 9. pp. 3453-3466.
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abstract = "Data from preclinical and clinical studies have demonstrated that granulocyte macrophage colony-stimulating factor (GMCSF) can function as a key proinflammatory cytokine. However, therapies that directly target GM-CSF function could lead to undesirable side effects, creating a need to delineate downstream pathways and mediators. In this work, we provide evidence that GM-CSF drives CCL17 production by acting through an IFN regulatory factor 4-dependent (IRF4-dependent) pathway in human monocytes, murine macrophages, and mice in vivo. In murine models of arthritis and pain, IRF4 regulated the formation of CCL17, which mediated the proinflammatory and algesic actions of GM-CSF. Mechanistically, GM-CSF upregulated IRF4 expression by enhancing JMJD3 demethylase activity. We also determined that CCL17 has chemokineindependent functions in inflammatory arthritis and pain. These findings indicate that GM-CSF can mediate inflammation and pain by regulating IRF4-induced CCL17 production, providing insights into a pathway with potential therapeutic avenues for the treatment of inflammatory diseases and their associated pain.",
author = "Adrian Achuthan and Cook, {Andrew D.} and Lee, {Ming Chin} and Reem Saleh and Khiew, {Hsu Wei} and Chang, {Melody W.N.} and Cynthia Louis and Fleetwood, {Andrew J} and Lacey, {Derek C.} and Christensen, {Anne D.} and Frye, {Ashlee T.} and Lam, {Pui Yeng} and Hitoshi Kusano and Koji Nomura and Nancy Steiner and Irmgard F{\"o}rster and Nutt, {Stephen L} and Moshe Olshansky and Turner, {Stephen J.} and Hamilton, {John A.}",
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Achuthan, A, Cook, AD, Lee, MC, Saleh, R, Khiew, HW, Chang, MWN, Louis, C, Fleetwood, AJ, Lacey, DC, Christensen, AD, Frye, AT, Lam, PY, Kusano, H, Nomura, K, Steiner, N, Förster, I, Nutt, SL, Olshansky, M, Turner, SJ & Hamilton, JA 2016, 'Granulocyte macrophage colony-stimulating factor induces CCL17 production via IRF4 to mediate inflammation', Journal of Clinical Investigation, vol. 126, no. 9, pp. 3453-3466. https://doi.org/10.1172/JCI87828

Granulocyte macrophage colony-stimulating factor induces CCL17 production via IRF4 to mediate inflammation. / Achuthan, Adrian; Cook, Andrew D.; Lee, Ming Chin; Saleh, Reem; Khiew, Hsu Wei; Chang, Melody W.N.; Louis, Cynthia; Fleetwood, Andrew J; Lacey, Derek C.; Christensen, Anne D.; Frye, Ashlee T.; Lam, Pui Yeng; Kusano, Hitoshi; Nomura, Koji; Steiner, Nancy; Förster, Irmgard; Nutt, Stephen L; Olshansky, Moshe; Turner, Stephen J.; Hamilton, John A.

In: Journal of Clinical Investigation, Vol. 126, No. 9, 01.09.2016, p. 3453-3466.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Granulocyte macrophage colony-stimulating factor induces CCL17 production via IRF4 to mediate inflammation

AU - Achuthan, Adrian

AU - Cook, Andrew D.

AU - Lee, Ming Chin

AU - Saleh, Reem

AU - Khiew, Hsu Wei

AU - Chang, Melody W.N.

AU - Louis, Cynthia

AU - Fleetwood, Andrew J

AU - Lacey, Derek C.

AU - Christensen, Anne D.

AU - Frye, Ashlee T.

AU - Lam, Pui Yeng

AU - Kusano, Hitoshi

AU - Nomura, Koji

AU - Steiner, Nancy

AU - Förster, Irmgard

AU - Nutt, Stephen L

AU - Olshansky, Moshe

AU - Turner, Stephen J.

AU - Hamilton, John A.

PY - 2016/9/1

Y1 - 2016/9/1

N2 - Data from preclinical and clinical studies have demonstrated that granulocyte macrophage colony-stimulating factor (GMCSF) can function as a key proinflammatory cytokine. However, therapies that directly target GM-CSF function could lead to undesirable side effects, creating a need to delineate downstream pathways and mediators. In this work, we provide evidence that GM-CSF drives CCL17 production by acting through an IFN regulatory factor 4-dependent (IRF4-dependent) pathway in human monocytes, murine macrophages, and mice in vivo. In murine models of arthritis and pain, IRF4 regulated the formation of CCL17, which mediated the proinflammatory and algesic actions of GM-CSF. Mechanistically, GM-CSF upregulated IRF4 expression by enhancing JMJD3 demethylase activity. We also determined that CCL17 has chemokineindependent functions in inflammatory arthritis and pain. These findings indicate that GM-CSF can mediate inflammation and pain by regulating IRF4-induced CCL17 production, providing insights into a pathway with potential therapeutic avenues for the treatment of inflammatory diseases and their associated pain.

AB - Data from preclinical and clinical studies have demonstrated that granulocyte macrophage colony-stimulating factor (GMCSF) can function as a key proinflammatory cytokine. However, therapies that directly target GM-CSF function could lead to undesirable side effects, creating a need to delineate downstream pathways and mediators. In this work, we provide evidence that GM-CSF drives CCL17 production by acting through an IFN regulatory factor 4-dependent (IRF4-dependent) pathway in human monocytes, murine macrophages, and mice in vivo. In murine models of arthritis and pain, IRF4 regulated the formation of CCL17, which mediated the proinflammatory and algesic actions of GM-CSF. Mechanistically, GM-CSF upregulated IRF4 expression by enhancing JMJD3 demethylase activity. We also determined that CCL17 has chemokineindependent functions in inflammatory arthritis and pain. These findings indicate that GM-CSF can mediate inflammation and pain by regulating IRF4-induced CCL17 production, providing insights into a pathway with potential therapeutic avenues for the treatment of inflammatory diseases and their associated pain.

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U2 - 10.1172/JCI87828

DO - 10.1172/JCI87828

M3 - Article

VL - 126

SP - 3453

EP - 3466

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 9

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