Vascular disease persistence in giant cell arteritis: are stromal cells neglected?

Abstract

Giant cell arteritis (GCA), the most common systemic vasculitis, is characterised by aberrant interactions between infiltrating and resident cells of the vessel wall. Ageing and breach of tolerance are prerequisites for GCA development, resulting in dendritic and T-cell dysfunction. Inflammatory cytokines polarise T-cells, activate resident macrophages and synergistically enhance vascular inflammation, providing a loop of autoreactivity. These events originate in the adventitia, commonly regarded as the biological epicentre of the vessel wall, with additional recruitment of cells that infiltrate and migrate towards the intima. Thus, GCA-vessels exhibit infiltrates across the vascular layers, with various cytokines and growth factors amplifying the pathogenic process. These events activate ineffective repair mechanisms, where dysfunctional vascular smooth muscle cells and fibroblasts phenotypically shift along their lineage and colonise the intima. While high-dose glucocorticoids broadly suppress these inflammatory events, they cause well known deleterious effects. Despite the emerging targeted therapeutics, disease relapse remains common, affecting >50% of patients. This may reflect a discrepancy between systemic and local mediators of inflammation. Indeed, temporal arteries and aortas of GCA-patients can show immune-mediated abnormalities, despite the treatment induced clinical remission. The mechanisms of persistence of vascular disease in GCA remain elusive. Studies in other chronic inflammatory diseases point to the fibroblasts (and their lineage cells including myofibroblasts) as possible orchestrators or even effectors of disease chronicity through interactions with immune cells. Here, we critically review the contribution of immune and stromal cells to GCA pathogenesis and analyse the molecular mechanisms by which these would underpin the persistence of vascular disease.

Keywords: Fibroblasts; Giant Cell Arteritis; Inflammation; Vasculitis.

Figure 1

Ageing of the immune system and vessel wall and vascular breach leading to early inflammation. Vascular ageing and ageing of the immune system are key predisposing factors in GCA pathogenesis. The ageing vessel exhibits elastic fibre disruption and increased vascular stiffness. Further, immunosenescence is characterised by a reduction in thymic T-cell production, DC dysfunction and reduction in circulating naïve T-cells and Tregs. In addition, cellular senescence observed in fibroblasts endothelial cells and macrophages in GCA lesions, links with the production of proinflammatory cytokines as well as catabolic factors (MMPs and VEGF). Circulatory and adventitial CD4 and CD8 T-cells also demonstrate cell senescence. Repetitive infective strain on the immune system and inflammation associate with epigenetic modifications which are also linked to this process. Meanwhile, distinct mechanisms are implicated for vascular breach leading to early inflammation as observed in GCA vessels. These include. (i) Defective PD-1/PD-L1 immune checkpoints: GCA vasDCs express low levels of PD-L1 which results in recruitment, activation and retention of PD-1⁺CD4⁺ T-cells in GCA arteries. (ii) Defective CD155/CD96 immune checkpoint: GCA macrophages express low levels of the immunoinhibitory ligand CD155 and this allows for uncontrolled activation and proliferation of CD4⁺CD96⁺T-cells which infiltrate the vessel wall and produce effector cytokines (IL-9). (iii) Increased CD28 T-cell costimulation in GCA: there is aberrantly increased interaction between CD80/86 on vasDCs and CD28 on CD4⁺ T-cells leading to enhanced T cell effector functions and cytokine production (IL-21 and IFN-γ). (iv) Dysfunctional regulatory T-cells: aberrantly increased Notch4 signalling in GCA CD8⁺ Tregs leads to restriction of NOX2-exosomal release, hence failing to generate ROS required for modulation of CD4⁺ T-cell activity. (v) Aberrant activation of the VEGF/Jagged-1/Notch pathway. VEGF induces Jagged-1⁺ expression by ECs which then interact with NOTCH1⁺ T-cells resulting in T-cell polarisation (Th1/Th17). These polarised T-cells infiltrate and intensify vasculitic immune activity. (vi) Disruption of endothelial lining of the vasa vasorum due to increased production and activity of ROS and MMPs by immature neutrophils and monocytes, respectively. This culminates in immune cell infiltration. EC, endothelial cell; GCA, giant cell arteritis; IL, interleukin; MMPs, matrix metalloproteinases; NOX2, NADPH oxidase 2; ROS, reactive oxygen species; TNF-α, tumour necrosis factor alpha; Treg, regulatory T-cell; vasDC, vascular dendritic cell.

Figure 2

Vascular remodelling and maintenance of vascular disease activity. Clockwise: (i) T-cells are polarised into Th1 and Th17 cells with distinct cytokine profiles, with Th1 arm being steroid unresponsive. T_RM cells are also present in giant cell arteritis (GCA) vessels, but amenable to JAK-STAT inhibition. Fibroblast mediated by cytokine production promote T-cell polarisation. (ii) VSMCs, fibroblasts are activated by local cytokine milieu pathogenically transform along a differentiation axis to myofibroblasts and contribute to intimal hyperplasia. They are associated with the production of proinflammatory cytokines, chemokines and proteinases. GCA Fibroblasts express CD74⁺ suggestive of sentinel-like abilities and role in vascular disease activity. (iii) GCA tissue macrophages are heterogenous and spatially distributed in the vessel wall. The macrophage subtypes secrete distinct cytokine and growth factor profiles contributing differentially to the disruption of internal elastic lamina and intimal hyperplasia. (iv) The stem-like TCF1⁺CD4⁺ T-cells exhibit self-renewal capabilities and differentiate into cytotoxic T-cells, T_FH T-cells and cycling 1 and cycling 2 T-cells promoting vascular inflammation. (v) MAIT cells are present in GCA-affected vessels, proinflammatory (IFN-γ secretion) and are steroid unresponsive. DC, dendritic cell; GC, glucocorticoid; IFN-γ, interferon-gamma; IL, interleukin; MAIT cell, mucosal-associated invariant T cell; MMP, matrix metalloproteinase; MΘ, macrophages; ROS, reactive oxygen species; TCF1⁺CD4⁺ T-cells, T cell factor 1 expressing CD4⁺T cells; TCR, T cell receptor; T_RM, tissue resident memory cells; VSMC, vascular smooth muscle cell. Figures were created using BioRender.com