194. DISTRIBUTION OF MACROPHAGE SUBSETS IN TEMPORAL ARTERY BIOPSIES OF PATIENTS WITH GIANT CELL ARTERITIS

Abstract

Background: Giant cell arteritis (GCA) is a granulomatous vasculitis characterized by recruitment of T-cells and monocytes to the vessel wall. Upon recruitment, monocytes are activated and differentiate into macrophages. These lesional macrophages take on different phenotypes depending on cues from the microenvironment. These macrophages are known to produce pro-inflammatory cytokines, chemokines, matrix-metalloproteinases (MMPs), and growth factors contributing to amplification of the inflammatory response, vessel wall injury and remodeling. However, current knowledge regarding macrophage subsets in GCA lesions is limited. Objectives: To examine the distribution of macrophage subsets in GCA lesions. Methods: Immunohistochemistry was performed on consecutive sections of paraffin-embedded temporal arteries of biopsy-confirmed GCA patients (n = 11) with antibodies to selected markers of inflammation and tissue remodeling (Table 1). Positive cells were scored in three layers of the vessel wall (adventitia, media-intima, inner-intima) using a semi-quantitative scoring system. Expression by macrophages was confirmed by double staining with the macrophage transcription factor PU.1. Results: The pro-inflammatory marker CD64 and pro-inflammatory cytokines (IL-12, IL-23 and IL-1β) were strongly expressed by macrophages throughout the vessel wall, most prominently in the adventitia. However, subsets of these CD64+ macrophages also showed concomitant expression of the tissue remodelling markers CD206 and FR-β in specific compartments of the lesions. More specifically, CD206+ macrophages were mainly found along the media borders which co-localized with positive MMP-9 staining. Interestingly, FR-β positivity was also found in the inner-intima of TABs with a high degree of intimal hyperplasia. FR-β expression was significantly higher in the inner-intima region in TABs with massive intimal hyperplasia compared to TABs with mild intimal hyperplasia (p = 0.01). Conclusion: Based on the expression of markers of inflammation and tissue remodeling, different subsets of infiltrating macrophages can be distinguished. Macrophages in vascular lesions of GCA patients display a distinct spatial distribution pattern within the inflamed vessel wall (Figure 1). Adventitial macrophages express highest level of pro-inflammatory cytokines indicating pro-inflammatory functions of these macrophages. Co-localization of CD206 and MMP-9 along media borders indicates a role for CD206+ macrophages in collagen digestion and angiogenesis. Additionally, the association of increased numbers of FR-β+ macrophages with extensive intimal hyperplasia suggests that FR-β+ macrophages promote myofibroblast proliferation. Reference [1] Watanabe R, Maeda T, Zhang H, Berry GJ, Zeisbrich M, Brockett R, Greenstein AE, Tian L, Goronzy JJ, Weyand CM. MMP (Matrix Metalloprotease)-9-Producing Monocytes Enable T Cells to Invade the Vessel Wall and Cause Vasculitis. Circ Res. 2018 Aug 31;123(6):700-715. Disclosure of Interests: William Febry Jiemy: None declared, Yannick van Sleen: None declared, Annemieke Boots Grant/research support from: grant from MSD in 2010-2015, Consultant for: I was a consultant for Grunenthal Germany 2016-2017, Employee of: I was an employee of Organon, Shering-Plough and MSD from 1991-2011, Riemer Slart: None declared, Peter Heeringa: None declared, Elisabeth Brouwer Speakers bureau: Dr. Brouwer as an employee of the UMCG received speaker fees and consulting fees from Roche which were paid to the UMCG