Inflammation From Peripheral Organs to the Brain: How Does Systemic Inflammation Cause Neuroinflammation?

Abstract

As inflammation in the brain contributes to several neurological and psychiatric diseases, the cause of neuroinflammation is being widely studied. The causes of neuroinflammation can be roughly divided into the following domains: viral infection, autoimmune disease, inflammation from peripheral organs, mental stress, metabolic disorders, and lifestyle. In particular, the effects of neuroinflammation caused by inflammation of peripheral organs have yet unclear mechanisms. Many diseases, such as gastrointestinal inflammation, chronic obstructive pulmonary disease, rheumatoid arthritis, dermatitis, chronic fatigue syndrome, or myalgic encephalomyelitis (CFS/ME), trigger neuroinflammation through several pathways. The mechanisms of action for peripheral inflammation-induced neuroinflammation include disruption of the blood-brain barrier, activation of glial cells associated with systemic immune activation, and effects on autonomic nerves via the organ-brain axis. In this review, we consider previous studies on the relationship between systemic inflammation and neuroinflammation, focusing on the brain regions susceptible to inflammation.

Keywords: cytokines; microcyte; neuroinflammation; organ-brain axis; peripheral organs; systemic inflammation.

FIGURE 1

The real root of peripheral inflammation induced neuroinflammation. Right side: In the case of systematic inflammation, peripheral inflammation cytokines are produced. Those cytokines could flow into CNS directly or cause BBB leakage, finally cause pro-inflammation cytokine in the brain increasing. Left side: Those cytokines in CNS triggers inflammation by activating glial cells, causing glymphatic clearance dysfunction etc. Brown part: These factors may cause region-specific neuroinflammation. AQP4, Aquaporin 4; BBB, Blood-brain Barrier; C1q, Compliment 1q; CNS, Central nervous system; COX-2, Cyclooxygenase; Glu, Glutamate; HPA axis, Hypothalamic–pituitary–adrenal axis; IDO, Indoleaminepyrrole 2,3-dioxygenase; IL-1α, Interleukin-1α; NLRP-3, NACHT-LRR and pyrin (PYD) domain-containing protein-3; NO, Nitric oxide; NOS, Nitric oxide synthase; PGE-2, Prostaglandin E2; PNS, Peripheral nervous system; PSNS, parasympathetic nervous system; PVN, Perivascular macrophages; QA, Quinolinic acid; ROS, Reactive oxygen species; SNS, Sympathetic nervous system; TJ, Tight junction; TNF-α, Tumor necrosis factor-α; TRP, Tryptophan; 5-HT, 5-hydroxytryptamine.