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

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55 Citations (Scopus)

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

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