Neuroinflammation and Infection: Molecular Mechanisms Associated with Dysfunction of Neurovascular Unit

Abstract

Neuroinflammation is a complex inflammatory process in the central nervous system, which is sought to play an important defensive role against various pathogens, toxins or factors that induce neurodegeneration. The onset of neurodegenerative diseases and various microbial infections are counted as stimuli that can challenge the host immune system and trigger the development of neuroinflammation. The homeostatic nature of neuroinflammation is essential to maintain the neuroplasticity. Neuroinflammation is regulated by the activity of neuronal, glial, and endothelial cells within the neurovascular unit, which serves as a “platform” for the coordinated action of pro- and anti-inflammatory mechanisms. Production of inflammatory mediators (cytokines, chemokines, reactive oxygen species) by brain resident cells or cells migrating from the peripheral blood, results in the impairment of blood-brain barrier integrity, thereby further affecting the course of local inflammation. In this review, we analyzed the most recent data on the central nervous system inflammation and focused on major mechanisms of neurovascular unit dysfunction caused by neuroinflammation and infections.

Near‐Infrared Spectroscopy Reveals Brain Hypoxia and Cerebrovascular Dysregulation in Primary Biliary Cholangitis

“…Indeed, CECs exposed to the cytokines TNFα or interleukin‐6 express fewer interendothelial proteins and have greater reactive oxygen species generation, leading to increased BBB permeability . Furthermore, CECs can be activated by cytokines that are either present in the blood or released by circulating immune cells in intimate contact with CECs, to produce secondary signaling molecules (e.g., additional cytokines, prostaglandin E 2 , nitric oxide) which interact with cells within the brain to alter NVC responses . Consistent with this suggestion, in a mouse model of cholestatic liver disease, we have shown that activated monocytes within the cerebral circulation adhere to CECs and induce CEC activation through TNFα–TNF receptor‐1 interactions .…”

“…(37) Furthermore, CECs can be activated by cytokines that are either present in the blood or released by circulating immune cells in intimate contact with CECs, to produce secondary signaling molecules (e.g., additional cytokines, prostaglandin E 2 , nitric oxide) which interact with cells within the brain to alter NVC responses. (38,39) Consistent with this suggestion, in a mouse model of cholestatic liver disease, we have shown that activated monocytes within the cerebral circulation adhere to CECs and induce CEC activation through TNFα-TNF receptor-1 interactions. (40,41) This immune cell and TNFα-driven CEC activation up-regulates CECs' inducible nitric oxide synthase expression and is directly linked to activation of microglia within the brain (especially those cells in close proximity to blood vessels) (40) and ultimately to altered behaviors expressed by cholestatic mice.…”

Brain tissue transcriptomic analysis of SIV-infected macaques identifies several altered metabolic pathways linked to neuropathogenesis, and Poly (ADP-ribose) polymerases (PARPs) as potential therapeutic targets

“…This increased innate immune response led to consequent up-regulation of numerous genes within the neuroinflammation signaling pathway (z-score = 3.6), likely establishing inflammation processes in the frontal cortex of the SIV-infected DV macaques (Table S3). Neuroinflammation signaling pathway plays a key role in maintaining the homeostasis of CNS, functioning to remove damaging agents, such SIV in this case, and clear injured neural tissues (Tohidpour et al, 2017). Excessive cell and tissue damage can ensue recruitment of microglia and enhancement of their activities, which exacerbates neuronal damage and ultimately results in chronic inflammation with necrosis of glial cells and neurons (Wang et al, 2015).…”

The intestinal microbiome and Alzheimer's disease: A review

“…Neuroinflammation triggered by pro‐inflammatory molecules causes increased permeability of the BBB, resulting in immune cell infiltration, exacerbation of the inflammatory response, leading to reactive gliosis, and eventually causing neurodegeneration . Bacteroidetes is a family of Gram‐negative bacteria, and thus have lipopolysaccharide (LPS) as the major outer membrane component, which can trigger systemic inflammation and promote the release of pro‐inflammatory cytokines .…”