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

Abstract

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.

Need and value of targeted immunosuppressive therapy in giant cell arteritis

“… 13 GM-CSF-skewed, CD206+MMP9+ macrophages in the TA express high levels of YKL-40 which may stimulate tissue destruction and angiogenesis through IL-13receptor α2 signalling. 14 Targeting GM-CSF or YKL-40 may thus inhibit macrophages that are currently insufficiently suppressed by GC. B cells are present in the adventitia and media of both TA and aorta GCA, where they can organise in tertiary lymphoid organs.…”

Functionally Heterogenous Macrophage Subsets in the Pathogenesis of Giant Cell Arteritis: Novel Targets for Disease Monitoring and Treatment

“…Recently, our group reported a distinct spatial distribution of CD206+/YKL-40+/MMP-9+ macrophages and FRβ+/CD206-macrophages linked to tissue destruction and intimal hyperplasia, respectively, in GCA [35]. The observed macrophage phenotypic heterogeneity is likely caused by the local production of GM-CSF and M-CSF.…”

“…Platelet-derived growth factor (PDGF), which is produced by macrophages, promotes VSMC and fibroblast migration and proliferation leading to intimal hyperplasia and eventually vessel-wall occlusion. (Figure 1) Furthermore, activated macrophages are the main contributors to tissue destruction by producing matrix metalloproteinases (MMPs) [33][34][35]. Therefore, gaining a deeper understanding of monocyte and macrophage involvement in GCA pathogenesis is vital.…”

“…In addition, tissue migrated monocytes/macrophages may aid the migration of T-cells to the vessel wall as well, through their production of MMP-9, which breaks down the extracellular matrix [41]. Further evidence indicates that the non-classical monocyte subset is the main source of MMP-9 and associated enzymes, in addition to pro-angiogenic factors such as YKL-40 [35,42,43]. Moreover, (classical) monocytes of GCA patients show upregulated CD64 expression but lowered expression of folate receptor β, which is likely a sign of an activated phenotype [41,44].…”

From Active to Non-active Giant Cell Arteritis: Longitudinal Monitoring of Patients on Glucocorticoid Therapy in Combination With Leflunomide

“…The source of CHI3L1 in serum of GCA patients might stem from monocytes, macrophages and giant cells ( 30 ). Additionally, CHI3L1 is highly expressed in TABs of GCA patients, predominantly in the intima-media border region ( 30 , 31 ). CHI3L1 is involved in tissue remodeling and angiogenesis ( 32 ), and deregulation of these processes in GCA TABs might contribute to increased amounts of CHI3L1 in occluded temporal arteries.…”