15 General introduction receptors (PRRs) such as Toll-like receptors (TLRs), as well as a range of receptors for inflammatory mediators such as IL-4, IL-6, IL-7, IL-10, IL-11, IL-12, and IL-1866-70. As microglia are the primary immune cells of the CNS, cross-talk between oligodendrocytes and microglia is a key area of interest in many CNS diseases71. Indeed, when oligodendrocytes are stressed they may be triggered to produce CXCL10, CCL2, and CCL3 to attract microglia to the area of damage72,73. Stressed oligodendrocytes upregulate HSPB5 (also known as αB-crystallin), a molecule that is reported to activate microglia74, is involved in immunoregulatory functions, and reduces clinical symptoms and tissue damage75. While astrocytes are increasingly implicated in being involved in immune functions the cross talk between oligodendrocytes and astrocytes is a relatively unexplored field. Imaging and monitoring neuroinflammation Over the last decades there have been significant advances in imaging techniques to visualise the brain during health and disease. One of the main challenges with developing current therapies for neurodegenerative and neuroinflammatory diseases is to monitor the efficacy and impact of the drug on the pathological processes in the CNS. Biomarkers of neuroinflammation and innate immune processes are considered essential for monitoring disease diagnosis, progression, and response to therapy, however there is a lack of accurate and reliable biomarkers for many neurological diseases76. Generally, blood and CSF are commonly used to monitor neuroinflammation, however in vivo imaging the CNS during disease has become a more widely accepted approach due to its ability to provide region-specific information as well as being minimally invasive depending on the technique. Such techniques include magnetic resonance imaging (MRI), positron emission tomography (PET), single photon emission computed tomography (SPECT), and optical imaging85. These approaches allow the study of some aspects of neuroinflammation: a) monitoring activation of resident CNS immune cells e.g. microglia activation, b) BBB permeability e.g. upregulation of adhesion molecules, c) CNS infiltration of immune cells and, d) pathology as a result of neuroinflammation e.g. demyelination and cell death (Table 2). In addition, aspects of BBB integrity, regarded as a hallmark of neuroinflammation, is imaged by leakage of gadolinium using MRI, or by nuclear imaging of P-gp and vascular cell adhesion molecule (VCAM-1), which are differentially expressed in MS86, stroke87, AD and vascular dementia88. Indicators of leukocyte function include markers of oxidative stress, such as proinflammatory and oxidative enzymes secreted by activated monocytes and neutrophils. One such product is myeloperoxidase (MPO) that can be detected by gadolinium (MPO-Gd) to track the oxidative activity of MPO non-invasively. Thus MPO has been used as a potential biomarker of neuroinflammation in experimental models of MS, namely experimental autoimmune encephalitis (EAE)89, and experimental stroke90. Cell-labelling approaches include radiolabeled antibodies and radiolabelled cytokines, which are imaged using SPECT, PET or optical imaging. For example, anti-CD3, anti-CD4, IL-1 and IL-2 have all been used to visualise receptors on T-lymphocytes in MS91 and rheumatoid arthritis92. As well as ongoing neuroinflammation, several approaches image the resultant pathology. As an example, PET ligands have been used to visualise myelin damage in MS93,94 while many approaches are used to visualise cell death e.g. neuronal loss, such as annexin-V, caspases and ML-10 85. Imaging of neuro-inflammatory biomarkers is an expanding topic with the potential to expedite diagnosis and improve disease and therapeutic monitoring. While many approaches are examined in preclinical models, fewer are available for studies in humans76.
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