Inflammation in CNS neurodegenerative diseases

Abstract

Neurodegenerative diseases, the leading cause of morbidity and disability, are gaining increased attention as they impose a considerable socioeconomic impact, due in part to the ageing community. Neuronal damage is a pathological hallmark of Alzheimer's and Parkinson's diseases, amyotrophic lateral sclerosis, Huntington's disease, spinocerebellar ataxia and multiple sclerosis, although such damage is also observed following neurotropic viral infections, stroke, genetic white matter diseases and paraneoplastic disorders. Despite the different aetiologies, for example, infections, genetic mutations, trauma and protein aggregations, neuronal damage is frequently associated with chronic activation of an innate immune response in the CNS. The growing awareness that the immune system is inextricably involved in shaping the brain during development as well as mediating damage, but also regeneration and repair, has stimulated therapeutic approaches to modulate the immune system in neurodegenerative diseases. Here, we review the current understanding of how astrocytes and microglia, as well as neurons and oligodendrocytes, shape the neuroimmune response during development, and how aberrant responses that arise due to genetic or environmental triggers may predispose the CNS to neurodegenerative diseases. We discuss the known interactions between the peripheral immune system and the brain, and review the current concepts on how immune cells enter and leave the CNS. A better understanding of neuroimmune interactions during development and disease will be key to further manipulating these responses and the development of effective therapies to improve quality of life, and reduce the impact of neuroinflammatory and degenerative diseases.

Keywords: immune response; inflammation; microbiome; neuroprotection; repair.

Figure 1

Blood–central nervous system (CNS) barriers. The blood–brain barrier (BBB) (a) and blood–spinal cord barrier (BSCB) (that resembles the BBB, see text for details) limit potential immune cells (shown in the lumen of the blood vessel), antibodies and soluble factors entering the CNS in health. Likewise, while the choroid plexus (CP) also limits cell migration, evidence suggests that regulatory T‐cells enter the brain via the CP (b) during health in order to ensure surveillance of the CNS (see text for details). CSF, cerebrospinal fluid.

Figure 2

Immune responses in human and experimental inflammatory neurodegenerative disorders. B‐cells (arrows) are observed in white (a) and grey matter lesions (b) in multiple sclerosis (MS). (c) and (d) depict an MS leucocortical lesion. The white matter (WML) is associated with HLA ⁺ microglia (d, WML) in contrast to the lack of HLA ⁺ microglia in the grey matter (d, GML). A similar pattern of HLA ⁺ cells is seen in the white and grey matter in an X‐ALD case (e) and where peripheral macrophages infiltrate the white matter (f). Granulocytes (arrow) in suspected vasculitis cases (g). Ageing influences the activity of microglia in a mouse model of MS: microglia in the central nervous system (CNS) of young mice (h; Iba1 staining) are less active than in aged mice (i). In MS cases microglia in normal appearing white matter express P2Y12 (j) and TMEM119 (k). In progressive multifocal leucoencephalopathy astrocytes (l, arrow) and activated microglia/macrophages (m, arrow) are highly reactive in an area of demyelination. The paucity of astrocytic glial fibrillary acidic protein expression (red circle, n) is associated with an area of microglial activation (red circle, o) in acute haemorrhagic leucoencephalitis.

Figure 3

Proposed factors that influence the gut–brain axis in neuroinflammmatory disorders. Cross‐talk (arrows) between the gut and brain indicates that lifestyle and the environment influence brain function that feeds back to the gut brain axis. Altered gut microbiota composition as a result of lifestyle, for example, poor diet, stress, infection and other environmental factors, enhances the risk of neuroinflammatory disorders. During development maternal inflammation and caesarean section may influence brain development and microbiome of the fetus. Therapeutic approaches using faecal transplants, controlled and restricted diet and probiotics may help establish a healthy microbiome and therefore improve brain health.

Figure 4

Mechanisms of damage and therapeutic control of inflammation in neurodegenerative diseases. (1) In the central nervous system (CNS), damage to neurons or genetic mutations leads to accumulation of misfolded and aggregated proteins characteristic of many neurodegenerative diseases. Such damage‐associated molecular patterns (DAMPs) and pathogen‐associated molecular patterns (PAMPs) activate microglia and astrocytes to release pro‐inflammatory factors. Likewise, stressed neurons and glia release heat‐shock proteins (HSPs) in an effort to counter the formation of aggregated proteins. Some HSPs, for example, HSPB5, induce regulatory microglia and astrocyte phenotypes. Neuronal specific antibodies (2) activate the complement system or induce Fc receptor (FcR)‐mediated damage. (3) Natural killer (NK) and T‐cells damage neurons via MHC class‐I, CD8⁺ T‐cells or non‐classical MHC molecules. (4) Excessive production of glutamate together with reduced glutamate uptake by astrocytes leads to excitotoxic damage of neurons. (5) Macrophage/microglia activation triggers reactive oxygen (ROS) and nitrogen (NOS) species, MMPs, chemokines and cytokines known to damage axons and neurons. (6) B‐cells secrete pathogenic antibodies and toxic factors that damage axons and oligodendrocytes. Therapeutic approaches to control neuroinflammation include (A) anti‐CD20 antibodies to deplete B‐cells that play multiple roles in immune‐mediated neurodegeneration (see text for details). (B) IVIG and plasmapheresis block pathogenic antibodies, including those triggered by tumours as in paraneoplastic disorders. (C) Complement inhibitors control activity of complement, while (D) antioxidants and (E) calorie restriction reduce ROS and NO levels that contribute to neurodegeneration. (F) In multiple sclerosis (MS), inhibition of T‐ and B‐cells entry across the blood–brain barrier (BBB) into the CNS, for example, (G) Natalizumab (Tysabri^®), or immune therapies that deplete T‐ and B‐cells [Alemtuzumab (Lemtrada^®), or alter their function Glatiramer acetate (Copaxone^®)] in the periphery, or (H) block immune cell trafficking from the lymph nodes (FTY720, S1PR‐agonists) controls neuroinflammation in the CNS.