Inflammatory processes have recently been found to be involved in the etiopathology of most neurological diseases. This does not only account for the classical neuroimmunological diseases such as multiple sclerosis, but also to diseases like Alzheimers disease, ALS, epilepsy, movement disorders, stroke and migraine, conditions previously considered as “non-inflammatory”.
The normal adult central nervous system contains low or undetectable levels of most systemic inflammatory cells. In classic inflammatory disorders of the CNS, such as multiple sclerosis, various immune cells including T and B lymphocytes invade CNS from the outside, activating microglia on the inside. In acute insults such as traumatic brain injuries, stroke, and after long-lasting epileptic seizures, markers of inflammation are increased within minutes, followed by a cascade of immunologically induced changes. But also in diseases without any evidence of an acute insult like movement disorders, ALS and migraine, inflammatory changes including microglia activation are found and thought to be important for the etiopathology.
In epilepsy, inflammation can be either the cause or the consequence of the condition. There is emerging evidence that inflammatory markers like IL-1β, TNF, IL-6, prostaglandin E2 and the complement cascade are upregulated in microglia, astrocytes and neurons, and are involved in seizure generation. Secondly, seizures induce immediately a cascade of inflammatory responses. The consequences may be altered synaptic excitability leading to chronic epilepsy and pharmacoresistance.
In neurodegenerative diseases like Alzheimers disease, ALS and Parkinsons disease there is a strong interaction with the immune system, primarily microglia but also astrocytes. In Alzheimers disease, reactive astrocytes surrounding the amyloid plaque may secrete proinflammatory factors that could contribute to the breakdown of amyloid plaques. On the other hand, there is evidence that activated astrocytes secrete significant quantities of amyloid beta, increasing the amyloid burden. In Parkinsons disease, accumulation of proinflammatory cytokines have been found in the brain, confirming ongoing neuroinflammation. These inflammatory mediators may activate transcription factors, notably nuclear factor κB, Ying-Yang 1 (YY1), fibroblast growth factor 20 (FGF20), and mammalian target of rapamycin (mTOR), which then regulate downstream signaling pathways promoting death of dopaminergic neurons that are vulnerable to oxidative stress and inflammatory attack.
A large body of experimental data indicates that inflammatory cells are also involved in all stages of atherosclerosis development. Transendothelial migration of circulating monocytes represents a key event in the initiation of atherosclerotic plaque followed by differentiation of macrophages into proinflammatory cells expressing proinflammatory cytokines, particularly IL-1β and TNF-α.
In multiple sclerosis, there is prominent infiltration of various leukocyte subsets into the
CNS. Even when there is no significant inflammatory infiltrates there is intense activation of microglia with resultant elevation of many inflammatory mediators within the CNS. T lymphocytes gain entry to the brain and spinal cord via disruptions of the blood-brain barrier. Such autoreactive T cells recognize and attack myelin, and this starts a broad, multifocal immune activation in CNS with damaging effects. Demyelination and axonal death represent the end result. Immunoactive therapy is well eatablished for multiple sclerosis, and with marked variations in mode of action.
Neuroinflammation also has its upsides. Several neurotrophic factors are produced and inflammation can also regulate the production of growth factors. Inflammation may increase axonal regeneration and remyelination and promoteneurogenesis and neuroprotection. Balancing the positive and negative effects of neuroinflammation is therefore crucial.
In conclusion, inflammation is involved in all neurological diseases, both “inflammatory” and “non-inflammatory”. A better understanding of mechanisms involved will give new insights into the causes of neurological diseases and hopefully open completely new treatment strategies for the best of our patients.
The Local Organizing Committee, Oslo, Norway. Erik Taubøll, December 28, 2017.