Pathogenic role of monocytes/macrophages in large vessel vasculitis

Abstract

Vasculitis is an autoimmune vascular inflammation with an unknown etiology and causes vessel wall destruction. Depending on the size of the blood vessels, it is classified as large, medium, and small vessel vasculitis. A wide variety of immune cells are involved in the pathogenesis of vasculitis. Among these immune cells, monocytes and macrophages are functionally characterized by their capacity for phagocytosis, antigen presentation, and cytokine/chemokine production. After a long debate, recent technological advances have revealed the cellular origin of tissue macrophages in the vessel wall. Tissue macrophages are mainly derived from embryonic progenitor cells under homeostatic conditions, whereas bone marrow-derived circulating monocytes are recruited under inflammatory conditions, and then differentiate into macrophages in the arterial wall. Such macrophages infiltrate into an otherwise immunoprotected vascular site, digest tissue matrix with abundant proteolytic enzymes, and further recruit inflammatory cells through cytokine/chemokine production. In this way, macrophages amplify the inflammatory cascade and eventually cause tissue destruction. Recent studies have also demonstrated that monocytes/macrophages can be divided into several subpopulations based on the cell surface markers and gene expression. In this review, the subpopulations of circulating monocytes and the ontogeny of tissue macrophages in the artery are discussed. We also update the immunopathology of large vessel vasculitis, with a special focus on giant cell arteritis, and outline how monocytes/macrophages participate in the disease process of vascular inflammation. Finally, we discuss limitations of the current research and provide future research perspectives, particularly in humans. Through these processes, we explore the possibility of therapeutic strategies targeting monocytes/macrophages in vasculitis.

Keywords: giant cell arteritis; large vessel vasculitis; macrophages; monocytes; takayasu arteritis; vasculitis.

Figure 1

Microscopic image of giant cell arteritis. (A) Left temporal artery biopsy from 65-year-old woman with giant cell arteritis (Hematoxylin and eosin staining, x10). Lymphocytes and macrophages form granulomatous inflammation, and intimal hyperplasia causes narrowing of the blood lumen. (B) High power field image of the biopsy (Hematoxylin and eosin staining, x40). Red arrows show multinucleated giant cells.

Figure 2

Functionally heterogenous macrophages in giant cell arteritis. Vascular lesion of giant cell arteritis contains a variety of macrophage subsets, each with a characteristic distribution. (A) In non-inflamed artery, vascular dendritic cells (vasDCs) reside in the media-adventitial border. (B) In the initial phase, vasDCs initiate inflammatory cascade, and recruits T cells and monocytes through chemokines. Infiltrated monocytes are differentiated into CD206+MMP-9+ macrophages by GM-CSF released from activated T cells. TGFβ1-producing macrophages are also present in the adventitia. (C) In the early phase, CD206+MMP-9+ macrophages migrate to the media and the media-intima border. Adventitial inflammation is increased. (D) In the late phase, CD206+MMP-9+ macrophages often fuse to form multinucleated giant cells and produce M-CSF, which gives rise to FRβ+ PDGF-producing macrophages at the media-intima border. Multiple cytokines and TLR2 are thought to be involved in the formation of multinucleated giant cells. VEGF-producing macrophages are preferentially located in the tunica media and intima. It should be noted that these macrophage subsets are not completely distinct. FRβ, folate receptor β; GM-CSF, granulocyte macrophage-colony stimulating factor; IFN, interferon; M-CSF, macrophage-colony stimulating factor; MMP, matrix metalloproteinase; PDGF, platelet-derived growth factor; TGFβ1, transforming growth factor β1; VEGF, vascular endothelial growth factor.

Figure 3

Macrophages/giant cells are professional chemokine producers in giant cell arteritis. Macrophages/giant cells in the vascular lesion of giant cell arteritis actively engage in chemokine production. The released chemokines amplify vascular inflammation by mobilizing cells that express the corresponding chemokine receptors. CXCL9, 10, and 11 recruit Th1 cells and memory B cells through CXCR3 receptor on the cell surface. CCL3, 4, and 5 recruit T cells expressing CCR5. CCL2 recruits CCR2-expressing classical monocytes. CX3CL1 mediates non-classical monocyte mobilization through CX3CR1 receptor. CCL, C-C motif Chemokine Ligand; CXCL, C-X-C motif Chemokine Ligand; CXCR, C-X-C Motif Chemokine Receptor.

Figure 4

Possible therapeutic strategies for giant cell arteritis targeting monocytes and macrophages. Monocytes/macrophages from patients with giant cell arteritis have pleiotropic functions. Excess production of proinflammatory cytokines (IL-1β, IL-6, and TNFα), chemokines (CXCL9, 10, and 11), proteolytic enzymes (MMP-2 and MMP-9), colony stimulating factors (GM-CSF and M-CSF), growth factors (VEGF, FGF, PDGF) could be targeted by the corresponding inhibitors. Immune dysregulation by defective PD-L1 expression on monocytes/macrophages could be corrected by PD-L1 Fc. Janus kinase (JAK) inhibitors may directly suppress the function of monocytes/macrophages. CXCL, C-X-C motif Chemokine Ligand; CXCR, C-X-C Motif Chemokine Receptor; FGF, fibroblast growth factor; GM-CSF, granulocyte macrophage-colony stimulating factor; M-CSF, macrophage-colony stimulating factor; MMP, matrix metalloproteinase; PDGF, platelet-derived growth factor; PD-L1, programmed death ligand 1; VEGF, vascular endothelial growth factor.