Granulocyte macrophage colony-stimulating factor induces CCL17 production via IRF4 to mediate inflammation
Adrian Achuthan, … , Stephen J. Turner, John A. Hamilton
Adrian Achuthan, … , Stephen J. Turner, John A. Hamilton
Published August 15, 2016
Citation Information: J Clin Invest. 2016;126(9):3453-3466. https://doi.org/10.1172/JCI87828.
View: Text | PDF
Research Article Inflammation Article has an altmetric score of 3

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

×

Figure 2

CCL17 is required for GM-CSF–driven inflammatory pain and can induce such pain.

Options: View larger image (or click on image) Download as PowerPoint
CCL17 is required for GM-CSF–driven inflammatory pain and can induce suc...
(A–C) i.pl. injection of GM-CSF (20 ng) or saline in (A) WT mice treated with/without indomethacin (12.5 μg/paw i.pl. at 2 hours) (n = 10 per group), (B) WT and Ccl17E/E mice (n = 5 per group), and (C) WT mice treated with anti-CCL17 or isotype control (2 μg/paw i.pl. at t = 0) (n = 5 per group). Pain development (incapacitance meter — ratio of weight bearing on injected relative to noninjected hindlimb — a value of < 100 indicates pain) was measured. (D–F) i.pl. injection of CCL17 (50 ng) or saline in (D) WT mice treated with and without indomethacin (12.5 μg/paw i.pl. at t = 0) (n = 5 per group), (E) WT mice treated with/without the COX2 inhibitor, SC58125 (5 mg/kg i.p. at t = –30 minutes) (n = 10 per group), and (F) WT and GMCSF–/– mice. Pain development was measured. (n = 6 per group). Results are shown as mean ± SEM. P values were obtained using a 2-way ANOVA test. *P < 0.05; **P < 0.01; ***P < 0.001, WT saline vs. WT GM-CSF or WT CCL17 (+ vehicle). #P < 0.05; ##P < 0.01; ###P < 0.001, WT GM-CSF vs. Ccl17E/E GM-CSF; GM-CSF + isotype vs. GM-CSF + anti-CCL17 mAb; GM-CSF or CCL17 + vs. – indomethacin (Indo) or COX2 inhibitor. ζP < 0.05, GMCSF–/– saline vs. GMCSF–/– CCL17.