A Distinct Macrophage Subset Mediating Tissue Destruction and Neovascularization in Giant Cell Arteritis: Implication of the YKL-40/Interleukin-13 Receptor alpha 2 Axis

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OBJECTIVE: Macrophages mediate inflammation, angiogenesis and tissue destruction in giant cell arteritis (GCA). Serum levels of the macrophage-associated protein YKL-40 (chitinase-3 like-1), previously linked to angiogenesis and tissue remodeling, remain elevated in GCA despite glucocorticoid treatment. Here, we aimed to investigate the contribution of YKL-40 to vasculopathy in GCA.

METHODS: Immunohistochemistry was performed on GCA temporal artery biopsies (TABs; n=12) and aortas (n=10) for detection of YKL-40, its receptor IL-13Rα2, macrophage markers PU.1 and CD206, and the tissue-destructive protein MMP-9. Ten non-inflamed TABs served as controls. In vitro experiments with GM-CSF- or M-CSF-skewed monocyte-derived macrophages (GM-MØs or M-MØs) were conducted to study the dynamics of YKL-40 production. Next, silencing RNA (siRNA)-mediated knock-down of YKL-40 in GM-MØs was performed to study its effect on MMP-9 production. Finally, the angiogenic potential of YKL-40 was investigated by tube formation experiments using human microvascular endothelial cells (HMVECs).

RESULTS: YKL-40 was abundantly expressed by a CD206+MMP-9+ macrophage subset in inflamed TABs and aortas. GM-MØs of GCA patients, but not of healthy controls, released significantly higher levels of YKL-40, compared to M-MØs. In inflamed TABs, IL-13Rα2 was expressed by macrophages and endothelial cells. Functionally, knock-down of YKL-40 led to a 10-50% reduction in MMP-9 production by macrophages, whereas exposure of HMVECS to YKL-40 led to significantly increased tube formation.

CONCLUSION: In GCA, a GM-CSF-skewed, CD206+MMP9+ macrophage subset expresses high levels of YKL-40 which may stimulate tissue destruction and angiogenesis through IL-13Rα2 signaling. Targeting YKL-40 or GM-CSF may inhibit macrophages that are currently insufficiently suppressed by glucocorticoids.

Original languageEnglish
Pages (from-to)2327-2337
Number of pages11
JournalArthritis & Rheumatology
Issue number12
Early online date1-Nov-2021
Publication statusPublished - Dec-2021


  • IL-13

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