A Distinct Macrophage Subset Mediating Tissue Destruction and Neovascularization in Giant Cell Arteritis: Implication of the YKL‐40/Interleukin‐13 Receptor α2 Axis

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 protein 1), previously linked to angiogenesis and tissue remodeling, remain elevated in GCA despite glucocorticoid treatment. This study was undertaken to investigate the contribution of YKL‐40 to vasculopathy in GCA. METHODS: Immunohistochemistry was performed on GCA temporal artery biopsy specimens (n = 12) and aortas (n = 10) for detection of YKL‐40, its receptor interleukin‐13 receptor α2 (IL‐13Rα2), macrophage markers PU.1 and CD206, and the tissue‐destructive protein matrix metalloproteinase 9 (MMP‐9). Ten noninflamed temporal artery biopsy specimens served as controls. In vitro experiments with granulocyte–macrophage colony‐stimulating factor (GM‐CSF)– or macrophage colony‐stimulating factor (M‐CSF)–skewed monocyte‐derived macrophages were conducted to study the dynamics of YKL‐40 production. Next, small interfering RNA–mediated knockdown of YKL‐40 in GM‐CSF–skewed macrophages 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 temporal arteries and aortas. GM‐CSF–skewed macrophages from GCA patients, but not healthy controls, released significantly higher levels of YKL‐40 compared to M‐CSF–skewed macrophages (P = 0.039). In inflamed temporal arteries, IL‐13Rα2 was expressed by macrophages and endothelial cells. Functionally, knockdown 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+MMP‐9+ 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.