Distinct macrophage phenotypes skewed by local granulocyte macrophage colony-stimulating factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF) are associated with tissue destruction and intimal hyperplasia in giant cell arteritis

William F Jiemy*, Yannick van Sleen, Kornelis Sm van der Geest, Hilde A Ten Berge, Wayel H Abdulahad, Maria Sandovici, Annemieke Mh Boots, Peter Heeringa, Elisabeth Brouwer

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

Objective: To determine the presence and spatial distribution of different macrophage phenotypes, governed by granulocyte macrophage colony-stimulating factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF) skewing signals, in giant cell arteritis (GCA) lesions.

Methods: Temporal artery biopsies (TABs, n = 11) from treatment-naive GCA patients, aorta samples from GCA-related aneurysms (n = 10) and atherosclerosis (n = 10) were stained by immunohistochemistry targeting selected macrophage phenotypic markers, cytokines, matrix metalloproteinases (MMPs) and growth factors. In vitro macrophage differentiation (n = 10) followed by flow cytometry, Luminex assay and ELISA were performed to assess whether GM-CSF and M-CSF are drivers of macrophage phenotypic heterogeneity.

Results: A distinct spatial distribution pattern of macrophage phenotypes in TABs was identified. CD206+/MMP-9+ macrophages were located at the site of tissue destruction, whereas FRβ+ macrophages were located in the inner intima of arteries with high degrees of intimal hyperplasia. Notably, this pattern was also observed in macrophage-rich areas in GCA aortas but not in atherosclerotic aortas. Flow cytometry showed that GM-CSF treatment highly upregulated CD206 expression, while FRβ was expressed by M-CSF-skewed macrophages, only. Furthermore, localised expression of GM-CSF and M-CSF was detected, likely contributing to macrophage heterogeneity in the vascular wall.

Conclusions: Our data document a distinct spatial distribution pattern of CD206+/MMP-9+ macrophages and FRβ+ macrophages in GCA linked to tissue destruction and intimal proliferation, respectively. We suggest that these distinct macrophage phenotypes are skewed by sequential GM-CSF and M-CSF signals. Our study adds to a better understanding of the development and functional role of macrophage phenotypes in the pathogenesis of GCA and opens opportunities for the design of macrophage-targeted therapies.

Original languageEnglish
Article number1164
Number of pages16
JournalClinical & translational immunology
Volume9
Issue number9
DOIs
Publication statusPublished - 2020

Keywords

  • giant cell arteritis
  • granulocyte macrophage colony-stimulating factor
  • macrophages
  • macrophage colony-stimulating factor
  • vasculitis
  • FOLATE RECEPTOR-BETA
  • IN-VITRO
  • INTERFERON-GAMMA
  • POLYMYALGIA-RHEUMATICA
  • HUMAN MONOCYTES
  • PROLIFERATION
  • IMMUNOTOXIN
  • EXPRESSION
  • MIGRATION
  • ARTHRITIS

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