Aging-Related Vascular Inflammation: Giant Cell Arteritis and Neurological Disorders

Abstract

Aging is characterized by the functional decline of the immune system and constitutes the primary risk factor for infectious diseases, cardiovascular disorders, cancer, and neurodegenerative disorders. Blood vessels are immune-privileged sites and consist of endothelial cells, vascular smooth muscle cells, macrophages, dendritic cells, fibroblasts, and pericytes, among others. Aging also termed senescence inevitably affects blood vessels, making them vulnerable to inflammation. Atherosclerosis causes low-grade inflammation from the endothelial side; whereas giant cell arteritis (GCA) causes intense inflammation from the adventitial side. GCA is the most common autoimmune vasculitis in the elderly characterized by the formation of granulomas composed of T cells and macrophages in medium- and large-sized vessels. Recent studies explored the pathophysiology of GCA at unprecedented resolutions, and shed new light on cellular signaling pathways and metabolic fitness in wall-destructive T cells and macrophages. Moreover, recent reports have revealed that not only can cerebrovascular disorders, such as stroke and ischemic optic neuropathy, be initial or coexistent manifestations of GCA, but the same is true for dementia and neurodegenerative disorders. In this review, we first outline how aging affects vascular homeostasis. Subsequently, we review the updated pathophysiology of GCA and explain the similarities and differences between vascular aging and GCA. Then, we introduce the possible link between T cell aging, neurological aging, and GCA. Finally, we discuss therapeutic strategies targeting both senescence and vascular inflammation.

Pathogenic role of monocytes/macrophages in large vessel vasculitis

“…Furthermore, low grade inflammation caused by aging, which is called inflammaging, inevitably affects monocyte/macrophages, T cells, and vascular cells both in the circulation and in the vascular tissue (82, 83). Cellular senescence of immune cells is often linked to the senescenceassociated secretory phenotype, which could be implicated in the pathomechanisms of GCA (62,84).…”

Giant Multinucleated Cells in Aging and Senescence—An Abridgement

“…Vascular aging depends on immune cells and inflammaging, a low-grade inflammation resulting from long-term stimulation of the innate immune system [ 36 ]. GCA is an inflammatory vasculopathy of large- and medium-sized arteries [ 36 , 37 , 38 ]. Mitochondrial dysfunction, causing the excessive production of ROS, is a significant contributor to vascular aging.…”

“…Mitochondrial dysfunction, causing the excessive production of ROS, is a significant contributor to vascular aging. ROS induces senescence of vessel endothelial and smooth muscle cells, which acquire the SASP phenotype [ 37 , 39 , 40 ]. The first immune cells responding to SASP and its pro-inflammatory secretome are vascular dendritic cells (vasDCs), located in the vessel wall.…”

“…The cytokines released from the activated DCs recruit T cells and monocytes. Monocytes differentiate into macrophages, which phagocyte cell debris and release various signaling molecules, including VEGF, further enhancing vessel inflammation and over-proliferation of the myofibroblasts in the vessel wall intima [ 37 , 41 ]. Subsequently, the activated macrophages fuse into giant multinucleated cells (GMCs), which produce a massive amount of matrix metalloprotease-9 (MMP-9) and other proteolytic enzymes.…”

“…The resulting excessive digestion of the extracellular matrix disrupts the vessel wall, allowing infiltration by the T cells, and furthering the inflammation and the formation of the inflammation foci (granulomas). The ultimate result is a collapse of the inner elastic membrane and occlusion of the vessel lumen by overgrown muscle cells ( Figure 1 ) [ 37 , 38 , 42 , 43 ].…”