Neuroinflammation: An Integrating Overview of Reactive-Neuroimmune Cell Interactions in Health and Disease

Abstract

The concept of central nervous system (CNS) inflammation has evolved over the last decades. Neuroinflammation is the response of reactive CNS components to altered homeostasis, regardless of the cause to be endogenous or exogenous. Neurological diseases, whether traumatic, neoplastic, ischemic, metabolic, toxic, infectious, autoimmune, developmental, or degenerative, involve direct and indirect immune-related neuroinflammation. Brain infiltrates of the innate and adaptive immune system cells appear in response to an infective or otherwise noxious agent and produce inflammatory mediators. Mediators of inflammation include local and recruited cells and signals. Processes derived from extrinsic and intrinsic CNS diseases also elicit the CNS inflammatory response. A deeper understanding of immune-related inflammation in health and disease is necessary to find potential therapeutic targets for preventing or reducing CNS damage. This review is aimed at discussing the innate and adaptive immune system functions and their roles in regulating brain cell responses in disease and homeostasis maintenance.

Figure 1

Essential ways cytokines affect the brain. (1) De novo synthesis of cytokines in the CNS in homeostatic conditions is clear. (2) Peripheral cytokines can induce brain cytokine synthesis. Also, cytokines can act centrally via endothelial cells. Cytokine-endothelial cell interaction triggers the release of second messengers like nitric oxide (NO) and prostaglandins (PGS) with central effects. Hence, the signal mediated by a cytokine as IL-1β can be transduced from the periphery without crossing the BBB. (3) Systemic administration of IL-1β and TNF-α to experimental animals decreases BBB selectivity. Cytokines induce glial stimulation.

Figure 2

Schematic representation of ATIA as the proposed inflammation and hypoxia crossover.

Figure 3

Schematic representation of parenchyma and macrophage cell fate in hypoxia and oxidative stress-inflammation environment.

Figure 4

Hypoxic and nonhypoxic inflammation and neuroimmune interactions involved in the prohemostatic response in the CNS. Brain parenchyma, the functional tissue, comprises neurons and glia cells. Brain damage or trauma often leads to cognitive deterioration and/or motor disability with parenchyma structural alterations and eventual cell death. Triggering (1) nonhypoxic and (2) hypoxic reactive inflammation might subserve functional postinjury recovery. Oxidative stress by a high oxygen level induces a compensatory antioxidant response to cut out damage progression. At the other end, hypoxia (hypoxic stress) by a low oxygen level upregulates pathways involved in boosting the oxygen supply. In any case, a fault in oxygen homeostasis draws inflammation with immune cell infiltrates and resident glial cells to restore homeostasis. Light-blue arrow: regulation; red arrow: stimulation.

Figure 5

Complexity of brain cell interactions in scar formation and repair.