Ionizing Radiation-Induced Immune and Inflammatory Reactions in the Brain

Abstract

Radiation-induced late brain injury consisting of vascular abnormalities, demyelination, white matter necrosis, and cognitive impairment has been described in patients subjected to cranial radiotherapy for brain tumors. Accumulating evidence suggests that various degrees of cognitive deficit can develop after much lower doses of ionizing radiation, as well. The pathophysiological mechanisms underlying these alterations are not elucidated so far. A permanent deficit in neurogenesis, chronic microvascular alterations, and blood-brain barrier dysfunctionality are considered among the main causative factors. Chronic neuroinflammation and altered immune reactions in the brain, which are inherent complications of brain irradiation, have also been directly implicated in the development of cognitive decline after radiation. This review aims to give a comprehensive overview on radiation-induced immune alterations and inflammatory reactions in the brain and summarizes how these processes can influence cognitive performance. The available data on the risk of low-dose radiation exposure in the development of cognitive impairment and the underlying mechanisms are also discussed.

Keywords: cognitive effects; immune reactions; ionizing radiation; low-dose radiation; neuroinflammation.

Figure 1

Immune signaling in the healthy and irradiated brain. In the healthy brain (left panel), intact neurons express and secrete molecules (CD47, CD55, CD20, and CX3CL1), which maintain adjacent microglial cells in a resting state. Brain microvascular endothelial cells, also in a resting state allow the continuous flow of blood lymphocytes and myeloid cells. In the irradiated brain (right panel), radiation-induced direct cellular damage affects neurons and microglia. Neuronal damage leads to the secretion of pro-inflammatory cytokines by the neurons, which activate microglia (mechanism a). In microglia, radiation-induced DNA damage through the NFκB pathway leads to microglia activation (MHC, CD68 upregulation) and secretion of pro-inflammatory cytokines (mechanism a). Damaged neurons secrete high-mobility group protein 1 (HMGB1) in the extracellular environment, which is a ligand for TLR4 on the activated microglia. Damaged neurons also express calreticulin on their surface, which is sensed by activated microglia and induces phagocytosis of both damaged and healthy neurons (mechanism b). Irradiation increases the secretion of CCL2 by activated microglia and also upregulates CCR2 expression. CCL2 signaling is a chemoattractant for CCR2-expressing peripheral macrophages, which penetrate the blood–brain barrier (mechanism c). Radiation induces upregulation of adhesion markers [intercellular adhesion molecule 1 (ICAM-1), P-selectin] on brain microvascular endothelial cells. Peripheral lymphocytes and monocytes adhere to activated endothelial cells and transmigrate through the microvessel wall (mechanism d). Pro-inflammatory signals and HMGB1 emitted by damaged neurons and activated microglia activate brain-residing dendritic cells, which migrate to regional lymph nodes and induce immune activation (mechanism e).