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
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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Research Article Inflammation

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

Abstract

Data from preclinical and clinical studies have demonstrated that granulocyte macrophage colony-stimulating factor (GM-CSF) 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 chemokine-independent 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.

Authors

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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Figure 8

IRF4 is required for GM-CSF–driven inflammatory pain and GM-CSF–driven arthritic pain and disease.

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IRF4 is required for GM-CSF–driven inflammatory pain and GM-CSF–driven a...
(A and B) i.pl. injection of GM-CSF (20 ng) in WT and Irf4–/– mice. (A) Pain (incapacitance meter) and (B) footpad mRNA expression (qPCR) (4 hours) (n = 6 per group). (C) Pain (incapacitance meter) following i.pl. CCL17 (50 ng) in WT and Irf4–/– mice (n = 5 per group). (D) Irf4 mRNA expression (day 7) in the joints of WT mice with mBSA/GM-CSF arthritis (n = 6 per group). (E and F) mBSA/GM-CSF arthritis was induced in WT and Irf4–/– mice and (E) pain and arthritis (histology, day 7) and (F) joint Ccl17 mRNA expression (day 7) were measured (n = 6 per group). (G) mBSA/CCL17 arthritis model was induced in WT and Irf4–/– mice, and pain and arthritis (histology, day 7) were measured (n = 6 per group). Original magnification, ×125. Results are shown as mean ± SEM. P values were obtained using a 2-way ANOVA test (A, C, D, E, F, G) and a t test (B). *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001, WT saline vs. WT GM-CSF or WT CCL17; ##P < 0.01 ###P < 0.001; ####P < 0.0001, WT GM-CSF vs. Irf4–/– GM-CSF; ζζP < 0.01, Irf4–/– saline vs. Irf4–/– CCL17.