Systemic Inflammation and the Brain: Novel Roles of Genetic, Molecular, and Environmental Cues as Drivers of Neurodegeneration

Abstract

The nervous and immune systems have evolved in parallel from the early bilaterians, in which innate immunity and a central nervous system (CNS) coexisted for the first time, to jawed vertebrates and the appearance of adaptive immunity. The CNS feeds from, and integrates efferent signals in response to, somatic and autonomic sensory information. The CNS receives input also from the periphery about inflammation and infection. Cytokines, chemokines, and damage-associated soluble mediators of systemic inflammation can also gain access to the CNS via blood flow. In response to systemic inflammation, those soluble mediators can access directly through the circumventricular organs, as well as open the blood–brain barrier. The resulting translocation of inflammatory mediators can interfere with neuronal and glial well-being, leading to a break of balance in brain homeostasis. This in turn results in cognitive and behavioral manifestations commonly present during acute infections – including anorexia, malaise, depression, and decreased physical activity – collectively known as the sickness behavior (SB). While SB manifestations are transient and self-limited, under states of persistent systemic inflammatory response the cognitive and behavioral changes can become permanent. For example, cognitive decline is almost universal in sepsis survivors, and a common finding in patients with systemic lupus erythematosus. Here, we review recent genetic evidence suggesting an association between neurodegenerative disorders and persistent immune activation; clinical and experimental evidence indicating previously unidentified immune-mediated pathways of neurodegeneration; and novel immunomodulatory targets and their potential relevance for neurodegenerative disorders.

Peripheral T-lymphocyte and natural killer cell population imbalance is associated with septic encephalopathy in patients with severe sepsis

“…Lipopolysaccharide stimulation has previously been reported to induce the release of proinflammatory and anti-inflammatory cytokines, in addition to their receptors, from a number of nervous system-associated cells, including neurones, astrocytes and microglia (41,42). This coexpression of proinflammatory and anti-inflammatory cytokines indicates that the immune system is highly regulated within the brain.…”

Role of Nitric Oxide Synthase in the Function of the Central Nervous System under Normal and Infectious Conditions

“…During a systemic response to infections, cytokines, chemokines, and damage-associated soluble mediators of systemic inflammation can gain access to the CNS via blood flow [40]. These mediators can access the brain tissue after the disruption of the BBB.…”

“…These mediators can access the brain tissue after the disruption of the BBB. The presence of proinflammatory mediators leads to a disturbance of neuronal and glial homeostasis, with subsequent cognitive and behavioral manifestations that are common during acute infections (anorexia, malaise, depression, and decreased physical activity) and are collectively known as sickness behavior [40]. Although sickness behavior manifestations are transient and self-limited, the cognitive and behavioral changes can become permanent or long-lasting under a persistent systemic inflammatory response.…”

“…Systemic inflammatory conditions result in the disruption of the BBB and the efflux of proinflammatory cytokines/chemokines as well as pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPS), which together activate glial cells. This results in an inflammatory environment due to the release of cytokines/chemokines and reactive oxygen/nitrogen species that exert direct and indirect neuronal cytotoxic effects [40,41]. Oligodendroglial myelin sheaths can be affected, thereby leading to axonal degeneration.…”

Breathlessness and inflammation: potential relationships and implications

“…In the long-term, however, chronic activation of this state may result in significant tissue damage. Accordingly, chronic systemic inflammation has been associated with a wide range of diseases including COPD (13)(14)(15)(16)(17)(18), heart failure (19,20), metabolic syndrome (21), and autoimmune disorders such as multiple sclerosis and SLE (22). It has also been linked to the development of psychiatric disorders such as depression and bipolar disorder (23).…”