Background/Purpose: Giant cell arteritis (GCA) is a large-vessel vasculitis affecting individuals over 50 years of age. Current models implicate genetic susceptibility, immune senescence, activation of vascular dendritic cells, and recruitment of CD4+ T cells driving inflammation via IFN-γ and IL-17. These cytokines stimulate vascular resident cells and recruit monocytes that differentiate into macrophages. While macrophages are consistently present in GCA lesions, their phenotypic heterogeneity and molecular drivers remain poorly characterized. Here, we explore macrophages landscape and heterogeneity in human temporal artery biopsies (TAB) from GCA patients to identify key regulators of myeloid cell response in GCA.

Methods: We analyzed blood and TAB from patients with biopsy-proven GCA and age-matched controls. Spatial transcriptomic profiling of TAB was performed using GeoMx and Visium HD plateforms. TREM-1 and TREM-2 protein expression was assessed by multiplex immunofluorescence (IF). Flow cytometry analyzed TREM-1 and TREM-2 expression on circulating monocytes, and serum soluble TREM-1 (sTREM-1) and sTREM-2 were measured by ELISA. In vitro functional analyses included THP-1-derived macrophages cultured and a TREM-1 inhibition assay using nangibotide.

Results: Spatial transcriptomics showed TREM-1 signaling among top upregulated pathways in media-infiltrating CD68⁺ macrophages from GCA lesions, alongside Th1, IL-6, and interferon signaling pathways, and identified IFN-γ and TLR activation as major upstream regulators using Ingenuity Pathway Analysis. The intima showed upregulation of myofibroblast-related genes, with causal network analysis predicted TREM-2 activation. High-resolution spatial transcriptomics (Visium HD) revealed SPP1⁺ TREM1⁺ inflammatory macrophages in the media, and MERTK⁺ FOLR2⁺ GPNMB⁺ TREM2⁺ macrophages in proximity to myofibroblasts. IF confirmed TREM-1 protein expression by most media-infiltrating CD68⁺ macrophages, while a smaller subset expressed TREM-2.Circulating monocytes expressed high TREM-1 and low TREM-2 in both GCA and controls. In contrast, serum sTREM-1 and sTREM-2 were significantly elevated in GCA patients (sTREM-1: 419.3 ± 30.5 vs. 224.9 ± 17.1 pg/mL, p< 0.0001; sTREM-2: 829.2 ± 106.4 versus 284.7 ± 26.6 pg/mL, p< 0,0001, for TREM-2), and sTREM-1 correlated with CRP (r=0.55, p< 0.01) and IL-6 (r=0.58, p< 0.01).In vitro, culture with IFN-γ/LPS increased proinflammatory genes and TREM1 in THP-1-derived macrophages, while IL-4/IL-13 - associated with an anti-inflammatory and pro-resolving phenotype - induced both TREM1 and TREM2 expression, suggesting a homeostatic role for TREM-2. Finally, nangibotide, a TREM-1 inhibitor, reduced THP-1 monocyte migration and decreased NFkB activation when added to IFN-γ/LPS-polarized THP-1-derived macrophages, suggesting a role for TREM-1 in macrophage recruitment and activation.

Conclusion: TREM-1 and TREM-2 define distinct macrophage subsets in GCA. TREM-1 is associated with inflammation and monocyte recruitment, while TREM-2 may mediate homeostatic functions. These findings position TREM-1 as a promising therapeutic target.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/spatially-resolved-transcriptomics-reveal-macrophage-heterogeneity-in-giant-cell-arteritis/