Neuroinflammation: the devil is in the details

Abstract

There is significant interest in understanding inflammatory responses within the brain and spinal cord. Inflammatory responses that are centralized within the brain and spinal cord are generally referred to as 'neuroinflammatory'. Aspects of neuroinflammation vary within the context of disease, injury, infection, or stress. The context, course, and duration of these inflammatory responses are all critical aspects in the understanding of these processes and their corresponding physiological, biochemical, and behavioral consequences. Microglia, innate immune cells of the CNS, play key roles in mediating these neuroinflammatory responses. Because the connotation of neuroinflammation is inherently negative and maladaptive, the majority of research focus is on the pathological aspects of neuroinflammation. There are, however, several degrees of neuroinflammatory responses, some of which are positive. In many circumstances including CNS injury, there is a balance of inflammatory and intrinsic repair processes that influences functional recovery. In addition, there are several other examples where communication between the brain and immune system involves neuroinflammatory processes that are beneficial and adaptive. The purpose of this review is to distinguish different variations of neuroinflammation in a context-specific manner and detail both positive and negative aspects of neuroinflammatory processes. In this review, we will use brain and spinal cord injury, stress, aging, and other inflammatory events to illustrate the potential harm and benefits inherent to neuroinflammation. Context, course, and duration of the inflammation are highly important to the interpretation of these events, and we aim to provide insight into this by detailing several commonly studied insults. This article is part of the 60th anniversary supplemental issue.

Keywords: astrocytes; lipopolysaccharide; microglia; neuroinflammation; sickness behavior.

Figure 1. Positive and Negative Aspects of Neuroinflammation

The intensity and duration of inflammation account for much of whether immune signals are supportive or destructive to the central nervous system. On the left, we show examples of brief and controlled inflammatory responses that are generally considered beneficial to the host organism. For instance, immune-to-brain signals after infection lead to the subsequent reorganization of host priorities and induction of sickness behaviors. Additionally, there is an important maintenance role of IL-1 and IL-4 on learning and memory. Following traumatic CNS injury, IL-4-driven repolarization of macrophages (M2) has been proven to be highly effective in promoting recovery and axonal regrowth. Immune preconditioning, or euflammation, provides a method for training the innate immune system toward a more neuro-protective phenotype. Conversely, on the right we demonstrate various maladaptive inflammatory responses. Chronic, uncontrolled inflammation is characterized by increased production of cytokines (IL-1 and TNF), reactive oxygen species (ROS), and other inflammatory mediators (inducible nitric oxide synthase). These markers are highly evident following trauma to the CNS, and are accompanied by significant recruitment and trafficking of peripheral macrophages and neutrophils to the site of injury. The transient inflammation after repeated social defeat stress also leads to monocyte and macrophage recruitment and causes anxiety and depression. Additionally, a low-level and chronic inflammatory response driven by IL-1 and IL-6 is caused by aging, follows the acute phase of CNS trauma, and leads to reduced neuronal plasticity and cognitive impairments. A higher degree of chronic inflammation is greatly damaging to the nervous system and is characteristic of neurodegenerative diseases.