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.

Keywords: HMGB1; TNF; anti-brain antibodies; autoimmune disorders; connectome; neurodegeneration; systemic inflammation and sepsis.

Figure 1

Brain milieu changes in response to systemic inflammation. Under healthy conditions the main cell types present in the brain are neurons, oligodendrocytes, astrocytes, and microglia. Neurons connect to each other through long axonal processes with synapses. Oligodendrocytes support axons with myelin sheaths. Astrocytes interact with blood vessels to form the blood–brain barrier and maintain neuronal synapses. Microglia form long processes that surveillance the brain and phagocytose apoptotic cells and prune inactive synapses without induction of inflammation. Under inflammatory conditions several mechanisms lead to neurodegeneration. Peripheral immune cells and inflammatory molecules traverse the blood–brain barrier exerting direct and indirect neuronal cytoxicity. Oligodendroglial myelin sheaths can be affected leading to axonal degeneration. Astrocytosis leads to reduced blood–brain barrier and synaptic maintenance. Microgliosis leads to a pro-inflammatory microglial phenotype with reduced phagocytic and tissue maintenance functions.

Figure 2

Connectome of the human brain. The human brain is organized as a small-world network. Neurons (black dots) form functional modules (gray shaded area). Within such modules, high connectivity is established by short intramodular connections (black lines). Additionally, long intermodular connections located in the white matter (red lines in yellow shaded area) connect different modules with each other. Small-world networks ensure parallel processing of different modes of information within specialized functional modules. Long intermodular connections (red lines) integrate different kinds of information to code a complex response by the brain. The “wiring cost” of neuronal connections is determined by the energetic requirements to maintain these connections. Short intramodular connections have low wiring costs (black line). Long intermodular connections ensure high network efficiency through parallel information processing at the expense of high wiring costs (red line). High wiring cost renders long intermodular connections (red lines) susceptible to energetic imbalance caused by systemic inflammation. Figure modified after Watts and Strogatz (1998).

Figure 3

Inflammation leads to neurodegeneration: a simplified model. Pathogen- or damage-derived antigens released in sufficient quantity activate systemic inflammation. In turn, peripheral (e.g., monocytes) as well as central (e.g., microglia) immune cells activate, increasing the production and release of inflammatory cytokines, chemokines, and other immunologically active peptides. Those mediators can induce neuronal dysfunction directly or indirectly, by interfering with neuronal homeostasis or disrupting the neuronal milieu. The end-result is a continuum of clinical manifestations from local and transient, to diffuse and persistent.