The inflammatory response is an early, non-specific immune reaction to tissue damage or pathogen invasion. Originally described as rubor, calor, tumor, and dolor (redness, heat, swelling, and pain) by Celsus in 1600,1 we now know these characteristics of inflammation are due to increased vascular permeability accompanied by a flux of cytokine-releasing phagocytic cells to the site of injury. Usually the inflammatory event is self-limiting as delayed endogenous release of anti-inflammatory molecules limits the duration of pro-inflammatory cytokine action. However, persistence of an antigen (foreign or self) leads to sustained and clustered macrophage activation, a hallmark of chronic inflammation. In addition to cytokines and microbicidal agents that lead to pathogen clearance and tissue repair, the activated macrophages secrete proteolytic enzymes, reactive oxidative species, and secondary intermediates that can cause damage to healthy tissue.1, 2, 3, 4 The numerous diseases associated with chronic inflammation suggest that this lack of resolution may switch the inflammatory response from protective to destructive.
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|Figure 1. beta-amyloid plaques induce neuroinflammation as characterized by glial activation and elevation in local pro-inflammatory cytokine production. Recent experiments have reported that transgenic overexpression of human interleukin-1 beta restricted to the mouse hippocampus is associated with neutrophil recruitment and increased clearing of plaques, highlighting a benefit of the neuroinflammatory response.13, 14|
Inflammation of the central nervous system (CNS) is of particular interest since the normal mammalian CNS is considered "immunoprotected" with relatively few resident immune cells and a highly specific blood-brain barrier (BBB). Pattern recognition receptors expressed primarily on microglia, the resident macrophages of the brain, are the initial responders to tissue insult or damage. In concert with astrocytes, reactive microglia produce numerous molecules to recruit other glial cells and peripheral immune cells to the site of injury.5 Increased glial activation, pro-inflammatory cytokine concentration, BBB permeability, and leukocyte invasion are common events following brain injury and have been documented in neurodegenerative diseases. One key player that is believed to drive this neuroinflammatory process is interleukin (IL)-1 beta, a pro-inflammatory cytokine that is upregulated in Alzheimer's disease (AD), Parkinson's disease, multiple sclerosis, and other neurodegenerative disorders.6, 7, 8 IL-1 beta signals through the type I IL-1 receptor/IL-1 accessory protein complex, leading to NFkB-dependent transcription of pro-inflammatory cytokines [tumor necrosis factor (TNF)-alpha, IL-6, and interferons] and neutrophil-recruiting chemokines (CXCL1 and CXCL2) in glia.9 IL-1 beta also stimulates production of tau and synaptophysin in neurons, two proteins associated with AD plaques.10 Whether chronic IL-1b elevation contributes to, or is a consequence of, brain pathology is difficult to determine due to the typical presence of both neuroinflammation and tissue damage upon post-mortem analysis. Animal models of experimental brain injury suggest that IL-1 beta-mediated leukocyte recruitment and other inflammatory events lead to neuronal cell death; however, few models incorporate long-term expression of this cytokine.11, 12
To better understand the role of IL-1 beta in chronic neuroinflammation, Shaftel and colleagues have described a transgenic mouse, IL-1 betaXAT, that utilizes the Cre/Lox system to initiate temporal and spatial expression of human IL-1 beta in the mouse brain.13 Unilateral induction of IL-1 beta gene expression in the hippocampus, a neural region critical for learning and memory, initiates a robust localized inflammatory response consisting of glial activation and inflammatory gene expression (IL-1 alpha, IL-1 beta, IL-6, TNF-alpha) that is present up to 10 months following intrahippocampal Cre recombinase injection.14 As predicted by the expression of chemokines CCL2/MCP-1, CXCL1/KC, and CXCL2/MIP-2, hippocampal IL-1 beta overexpression also stimulates localized leukocyte migration composed of CD4+CD8+ T cells, dendritic cells, and macrophages that is accompanied by BBB leakage. This migration is dependent on the chemokine receptor CXCR2. The number of CXCR2+ neutrophils remains elevated one year later, re-affirming the IL-1 betaXAT mouse as a suitable model of chronic neuroinflammation and leukocyte infiltration. However, in contrast to numerous studies implicating neutrophil invasion as a factor in neuronal death,15 IL-1 beta XAT mice show no evidence of neuronal cell loss or architectural compromise in the hippocampus at two months post-IL-1b induction. Although surprising, this result may simply suggest that sustained and elevated IL-1 beta in a normal brain by itself is not harmful; rather, IL-1 beta may be an accomplice under the influence of other existing factors.
Since the suggestion that rheumatoid arthritis patients treated with non-steroidal anti-inflammatory drugs (NSAIDs) have a lower incidence of Alzheimer's disease (AD),16 chronic neuroinflammation has been implicated in the stereotypical morphology of beta-amyloid plaques and fibrillary tangles found in AD.17 To address the impact of IL-1 beta in the face of AD-associated pathology, Shaftel et al. crossbred the IL-1 beta XAT mice with APP/PS1 mice, a transgenic model of AD characterized by accelerated plaque development.12 Despite previous brain injury studies reporting exaggerated damage in the presence of IL-1 beta,18 brains from APP/PS1 mice expressing the IL-1 betaXAT transgene show decreased beta-amyloid plaque frequency and load in the hippocampus. Further analysis of plaque-associated microglia reveals an increase in the number of overlapping microglia, suggesting an enhancement of microglia's phagocytic clearing of amyloid.19 These results suggest a beneficial role for IL-1 beta-mediated events in the AD brain. Furthermore, this study provides insight on the lack of clinical benefit of anti-inflammatory treatment in AD patients,20 drawing a distinction between the role of neuroinflammation in the development of beta-amyloid plaques versus being a consequence of these plaques.
In addition to identifying their presence in neurological disorder, understanding the expression of inflammatory molecules with respect to time and context of other biological and pathological events will be critical to maximizing the benefit of neuroinflammation while minimizing its potential harm.