Neuroinflammation: No Rose by Any Other Name

If you wrap up different kinds of furniture in enough wrapping paper, you can make them all look the same shape (12). The term “neuroinflammation” has become such a wrapping paper for an increasing number of etiologically distinct central nervous system (CNS) pathologies. As the first article (4) of this symposium explains: “Historically, the term ‘neuroinflammation’ was clearly defined and denoted immune-driven pathology in the brain. Unfortunately, this clarity has diminished in recent years. ” It has in fact diminished to the point that the designation “neuroinflammation” is effectively useless in practice because it denotes both true and pseudo-inflammation (5). Some recent, attentiongrabbing examples of the latter include air pollution, obesity and sleep loss (2, 3, 16). As of August 2014, there were 6249 publications and 118 894 citations on the topic of “neuroinflammation” (Figure 1), and the increase is steep. Are most or all of these papers missing the point? Certainly not all, but the problem with a “diagnosis” that has opposite meanings in the literature cannot be solved easily in the face of thousands of publications, many of which are conflicting but cannot realistically be corrected. Therefore, although the term “neuroinflammation” seems doomed for logical reasons alone, a serious effort needs to be made to achieve clarity regarding what the findings reported in these publications mean in the light of state-of-the-art concepts (14, 15). The occurrence of classical inflammation in the CNS is the backdrop against which any consideration of “neuroinflammation” of the non-autoimmune type (9) has to be viewed and judged. Classical inflammation occurs in the CNS like in any other organ and it shows essentially the same tissue characteristics. Multiple sclerosis is a prime example, as is its animal model, experimental autoimmune encephalomyelitis (EAE). The ensuing idea that inflammation should be recognizable beyond organ borders is strongly supported by recent in silico findings (5). In addition to autoimmune forms, other examples of true neuroinflammation in the CNS include acute and chronic infections, stroke and trauma to name the most important examples. In contrast, the tissue changes observed in Alzheimer’s disease, Parkinson’s disease and schizophrenia are not even remotely comparable. In other words, they are categorically different as confirmed by unsupervised hierarchical clustering of microarray data (5). Indeed, it has been fairly clear all along that a pathogenetic relationship between these diseases and inflammation was almost exclusively thought of by researchers far away from diagnostic neuropathology—and the relevant tissues to compare observations to. Thus, there can be little doubt that the confusion surrounding “neuroinflammation” is in no small part due to the fact that experienced neuropathologists who are capable of making the distinction between classical inflammation, sterile inflammation and microglial activation, gliosis, etc., are very rare compared with the many neuroscientists who study brain tissue because most countries still do not have the medical specialty. Instead, neuropathology is considered a luxury while funding is spent on more fashionable projects (see below). The absurdity of the current use of the term “neuroinflammation,” and equally a sign of the hype surrounding it, is perhaps best illustrated by the following quotation: “Neuroinflammation was one of the prominent pathological features described by Alois Alzheimer in his first case report in 1907” (10). Of course, Alois Alzheimer was not only unaware of the term but the Brain Pathology ISSN 1015-6305