oa Editorial [Hot Topic: Innate Immune Responses in CNS Neurodegenerative Diseases (Guest Editors: Hans van Noort and Sandra Amor)]

Inflammatory processes in the central nervous system (CNS) are of acute relevance to the pathogenesis and progression of several important neurological disorders. While multiple sclerosis (MS) is often quoted as one of the most striking examples of an inflammatory neurodegenerative condition, it is now widely recognized that inflammatory processes, particularly the innate immune responses, play a crucial role also in the pathogenesis of several other neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD). In addition, the clinical outcome of cerebrovascular disorders including stroke, and of acute brain and spinal cord injury is determined to a large extent by inflammatory processes which control resolution of damage, and subsequent repair. Thus, understanding inflammation and particularly the first steps in the process i.e. the innate inflammatory response in the CNS, is of central importance to understanding the nature of major neurological problems, and thus to effectively design ways to control them and treat disease. The neurodegenerative disorders mentioned above in which innate inflammation plays a crucial role represent the majority of chronic neurodegenerative disorders. When examined for their impact on disability-adjusted life years, a measure used by the World Health Organization [1] to assess the impact of various diseases, cerebrovascular disorders including stroke account for more than half the disease burden, while neurodegenerative conditions including AD, PD, and MS make up for another 15%. The contribution especially by various dementias to the global disease burden is expected to sharply rise over the next decades, due to, for example, the ageing of the population. Different from stroke or traumatic brain injury, the neurodegenerative conditions such as AD, PD and MS are not immediate killers, but rather these disorders reduce the quality of life over a much longer period of time. The worldwide prevalence of MS for example is estimated at around 0.01%, but its worldwide impact on disability-adjusted life years is ten times higher. Also since several neurological disorders are particularly prevalent in the more affluent regions of the world, with ageing populations, they represent targets of strong interest to the pharmaceutical industry. While neurological diseases account for about 6% of the global disease burden, the CNS drug market represents about twice this percentage of the global pharmaceutical market. The global market of MS drugs rapidly approaches 10 billion US dollars, which is around 1% of the total worldwide sales of pharmaceutics, ten times over what would be expected based on mere disease burden. Neurological diseases are clearly very attractive targets for drug development. This special issue in CNS & Neurological Disorders - Drug Targets, aims to reflect our growing understanding of innate immune processes in the brain and spinal cord. These processes are vital to maintain homeostasis in the CNS, to control infections and tumours that may emerge, and to initiate repair processes and regeneration after trauma. The inflammatory processes that will be discussed are pivotal to a number of neurological and neurodegenerative disorders. When considering innate immune responses in the CNS, one particular cell type attracts immediate attention. It is the brain macrophage, known as microglia. This relatively small cell that populates the entire CNS is a true sentinel. Microglia spend their life exploring their individual territories in the tissue. Like the brain they protect, it is used to an 8-hour working day, which is the time it takes for a single microglia to fully scan its environment. Microglia possess an impressive array of receptors to sense environmental signals, and they rapidly respond when they encounter anything out of the ordinary within their territory, be it the presence of danger or a stranger. Apart from the obvious role of microglia, however, essentially all cell types in the CNS are involved in controlling inflammatory processes. Astrocytes, oligodendrocytes, and also neurons themselves are all actively engaged in continuous surveillance and communication. A bewildering collection of receptors and ligands are expressed by all these cells, and are used to initiate, regulate, and inhibit inflammatory processes. In the first chapter of this issue, Jeffrey Bajramovic sheds light on the nature of cellular receptors involved in controlling inflammatory responses in the CNS, and the ligands that exist for these receptors. The well-known Toll-like receptors are among them, but there are many more receptors involved. Special attention is drawn to adenosine receptors, which have only recently been recognized for their pivotal contribution to inflammatory processes in the CNS. In addition, this first contribution emphasizes that many of the receptors involved in inflammatory pathways do not merely stimulate inflammatory responses by microglia, but are essential to the functions of other neural cells as well, and quite often crucial in inhibiting inflammation rather than stimulating it. This particular point is taken further in the second chapter, in which Philippe Gasque and colleagues introduce neuroimmune regulatory proteins. This group of surface-expressed proteins can be found on many different types of cells, and perform an array of intriguing functions. They regulate phagocytic activity by microglia, sequester and neutralize pro-inflammatory factors, and instigate recruitment of stem cells. Like several of the receptors described in the first chapter, neuroimmune regulatory proteins offer novel options as therapeutic targets. In chapter 3, ion channels are highlighted as another group of possible therapeutic targets. Stephen Skaper scrutinizes the role of microglial ion channels in different neuroinflammatory conditions. Evidence is presented for a close involvement of these ion channels in processes leading to neurodegeneration, including the processes culminating in AD or MS. This chapter supports the idea that blocking ion channels may help to inhibit exaggerated or chronic inflammation in the CNS, thus proving clearly defined targets for anti-inflammatory intervention. In the case of AD, both epidemiological and genetic evidence point to a contribution of inflammation to the disease process. Yet, antiinflammatory intervention in established disease has not yet produced the effects hoped for. In chapter 4, Jeroen Hoozemans and colleagues examine the role of inflammation in AD. Among the first to recognize the inflammatory component in the pathogenesis of AD, they examine current strategies to apply anti-inflammatory drugs to AD. This chapter makes the point that some of the key inflammatory events in AD actually precede clinical manifestation. It is therefore suggested that anti-inflammatory intervention may be more successful when applied as an early, preventive strategy. That anti-inflammatory strategies, i.e. simply blocking the activity of for example microglia, may not always be the best option, is further illustrated in chapter 5, which focuses on MS. In this chapter, Sandra Amor and Hans van Noort and colleagues explain how the destructive inflammatory process that causes MS is actually preceded by an initial stage of local mild inflammation in brain tissue which appears to be aimed at repair. Likely triggered by oligodendrocyte stress, microglia under these conditions do become activated, but not in a traditional destructive way. Instead, local signals, notably including small heat shock proteins, stimulate microglia to produce anti-inflammatory and reparative mediators, and almost all of these events of microglial activation appear to resolve spontaneously. Clearly, blocking microglial function at this stage would likely cause more harm than good....