Involvement of Monocyte Subsets in the Immunopathology of Giant Cell Arteritis

Elisabeth Brouwer,Johanna Westra,Peter Heeringa,Kornelis S M Van Der Geest,Wayel H Abdulahad,Annemieke M H Boots,Yannick Van Sleen,Qi Wang

doi:10.1038/s41598-017-06826-4

Elisabeth Brouwer, Johanna Westra + Show 6 more

Open Access

https://doi.org/10.1038/s41598-017-06826-4

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Abstract

Monocytes/macrophages are critical in systemic and local inflammation in giant cell arteritis (GCA) and possibly in clinically overlapping polymyalgia rheumatica (PMR). Therefore, we aimed to understand the contribution of monocyte subsets and the CX3CR1-CX3CL1 and CCR2-CCL2 migratory pathways, to the pathology of GCA. Peripheral blood monocytes were enumerated in samples from newly-diagnosed, untreated GCA and PMR patients and after prednisone-induced remission. The distribution of classical (CD14brightCD16neg) and the more pro-inflammatory, intermediate (CD14brightCD16+) and non-classical (CD14dimCD16+) monocyte subsets was analysed by flow cytometry. The phenotype of macrophages in temporal artery biopsies (TABs) from GCA patients was studied by immunohistochemistry and immunofluorescence. A clear monocytosis was seen in newly diagnosed GCA and PMR patients caused by elevated numbers of classical monocytes. Prednisone treatment suppressed numbers of non-classical monocytes. Both chemokine CX3CL1 and CCL2 were highly expressed in the TAB. Most macrophages in the TAB of GCA patients expressed non-classical monocyte markers CD16 and CX3CR1 whereas co-localisation of CD16 with classical monocyte marker CCR2 was infrequent. In conclusion, we report an altered distribution of monocyte subsets in both GCA and PMR patients. The majority of macrophages in TABs of GCA patients were CD68 + CD16 + CX3CR1 + CCR2− and thereby resembled the phenotype of non-classical monocytes.

Highlights

Giant cell arteritis (GCA) is an immune mediated vasculitis characterized by granulomatous infiltrates in the vascular wall of medium and large arteries causing vascular occlusion leading to blindness or stroke
Numbers of circulating monocytes as determined in a standard hematology counter were higher in newly diagnosed giant cell arteritis (GCA) and newly diagnosed polymyalgia rheumatica (PMR) patients compared to healthy controls (HC) (Fig. 1 and Tables 1 and S1)
As a clear monocytosis was observed in newly diagnosed GCA (nGCA)/newly diagnosed PMR (nPMR), we analysed the distribution of the three different monocyte populations defined by CD14 and CD16 expression (Fig. 2a)

Summary

Introduction

Giant cell arteritis (GCA) is an immune mediated vasculitis characterized by granulomatous infiltrates in the vascular wall of medium and large arteries causing vascular occlusion leading to blindness or stroke. An improved understanding of the immunopathogenesis of GCA and PMR may eventually lead to highly needed alternative treatment options for GCA and PMR patients. Within the vessel wall, migrated monocytes/ macrophages produce pro-inflammatory cytokines and matrix metalloproteases causing severe vascular damage. To study the contribution of monocytes/macrophages to the immunopathogenesis of GCA, it is crucial to understand the monocyte subsets as precursors of the tissue macrophages and their chemokine directed migration in this disease. The distribution of the three monocyte subsets in GCA and PMR patients has not been studied. As CD16+ monocytes are pro-inflammatory and increase with age, we hypothesized that these monocytes preferentially migrate to the vascular wall and contribute to GCA pathogenesis. We investigated expression of defined chemokine receptors and their ligands in peripheral blood of GCA and PMR patients and in temporal arteries of GCA patients

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