The Role of Immunosenescence in Cerebral Small Vessel Disease: A Review

Abstract

Cerebral small vessel disease (CSVD) is one of the most important causes of vascular dementia. Immunosenescence and inflammatory response, with the involvement of the cerebrovascular system, constitute the basis of this disease. Immunosenescence identifies a condition of deterioration of the immune organs and consequent dysregulation of the immune response caused by cellular senescence, which exposes older adults to a greater vulnerability. A low-grade chronic inflammation status also accompanies it without overt infections, an “inflammaging” condition. The correlation between immunosenescence and inflammaging is fundamental in understanding the pathogenesis of age-related CSVD (ArCSVD). The production of inflammatory mediators caused by inflammaging promotes cellular senescence and the decrease of the adaptive immune response. Vice versa, the depletion of the adaptive immune mechanisms favours the stimulation of the innate immune system and the production of inflammatory mediators leading to inflammaging. Furthermore, endothelial dysfunction, chronic inflammation promoted by senescent innate immune cells, oxidative stress and impairment of microglia functions constitute, therefore, the framework within which small vessel disease develops: it is a concatenation of molecular events that promotes the decline of the central nervous system and cognitive functions slowly and progressively. Because the causative molecular mechanisms have not yet been fully elucidated, the road of scientific research is stretched in this direction, seeking to discover other aberrant processes and ensure therapeutic tools able to enhance the life expectancy of people affected by ArCSVD. Although the concept of CSVD is broader, this manuscript focuses on describing the neurobiological basis and immune system alterations behind cerebral aging. Furthermore, the purpose of our work is to detect patients with CSVD at an early stage, through the evaluation of precocious MRI changes and serum markers of inflammation, to treat untimely risk factors that influence the burden and the worsening of the cerebral disease.

Astrocytic CXCL5 hinders microglial phagocytosis of myelin debris and aggravates white matter injury in chronic cerebral ischemia

“…Microglia and astrocytes play important roles in regulating the demyelination and remyelination process in CSVD. Therefore, controlling the microglia- and astrocyte-mediated chronic neuroinflammation is considered as an efficient therapeutic strategy for WMI [ 2 ]. For example, cornel iridoid glycoside reduced microglia-mediated inflammatory response via the NOD-like receptor thermal protein domain associated protein 3 (NLRP3)/calpain pathway and attenuated myelin loss and cognitive decline in a rat model of chronic cerebral ischemia [ 3 ].…”

Age-Related Alterations in Immune Function and Inflammation: Focus on Ischemic Stroke

“…The senescence cascade response of the immune system may exacerbate the alterations caused by brain aging and age-related neurological damage or disease [ 33 ]. Specifically, the architecture of lymphoid organs, where immune cells mature, develop, and reside, and the composition and function of cell subsets change with age [ 34 ]. Immunosenescence, which amplifies neuroinflammation, progressively alters and deteriorates the immune system over time and eventually causes negative consequences in older individuals, such as stroke [ 35 ].…”

Senescent Cells: Dual Implications on the Retinal Vascular System

“…Losing replicative potential inhibits cell endothelialization and declines the repair function of vessels [153]. The presence and accumulation of senescent vascular cells also results in a leaky and highly permeable endothelium, allowing immune cells and circulating non-immune cells to enter the surrounding tissue and provoke a low-grade inflammatory state [154][155][156]. In both in vivo and in vitro studies of the blood-brain barrier (BBB) model, the accumulation of senescent vascular cells is accompanied by lower barrier integrity [157].…”