14 Chapter 1 factor (BDNF) are important for learning and memory processes, a process that can be affected by maternal inflammation leading to disrupted behaviour and learning in later life52. On the other hand, monocytes are the blood-borne precursors to macrophages and dendritic cells, and play a key role in innate immunity although their distinct roles in CNS disorders are frequently hard to distinguish from microglia. The novel markers TMEM119 and P2Y12 have helped differentiate microglia and macrophages53, indicating that the relative contribution of these cells to neuroinflammatory diseases can be examined. However, microglia have been found to downregulate both TMEM119, and P2RY12 upon activation53, complicating the picture. A more recent study has found the enzyme HexB has high microglial specificity, during both health and disease54, a finding that may better clarify their role in health and disease in the future. Astrocytes While astrocytes were originally viewed as supportive cells for neurons, it is now clear that astrocytes perform a broad array of physiological and immunological functions in the CNS55-59. Similar to the M1/M2 polarization of macrophages and microglia, subpopulations of astrocytes have been reported that produce proinflammatory mediators (A1) and immunoregulatory mediators (A2). The A1 astrocytes that secrete IL-1a, TNF and C1q are considered to be neuroinflammatory, and damage neurons and oligodendrocytes in vitro as well as inducing apoptosis, suppress T helper cell activation, proliferation and function of activated T-cells, while in contrast, A2 astrocytes are neuroprotective, promoting neuronal growth, survival, and synaptic repair60. Astrocytes respond to a plethora of insults and are frequently observed as hypertrophic in many neurodegenerative diseases including stroke, TBI, MS, amyotrophic lateral sclerosis (ALS) and viral infections and other inflammatory conditions60. A1 reactive astrocytes have been suggested as having toxic effects in ALS, AD, MS, Parkinson’s disease (PD), Huntington’s disease (HD), schizophrenia and ageing60,61; whilst synapse-promoting A2 astrocytes may be responsible for unwanted synapses in epilepsy and neuropathic pain62. However, similar to recent advances in the microglial field, astrocytes should be considered to be more heterogeneous than A1 and A2. Multiple subtypes of astrocytes were identified using single cell RNA sequencing; each with their own distinct gene enrichment profile and physiological functions63. For example, different subtypes were found to contribute differentially to synaptogenesis which might be locally regulated by neuronal activity. More recently, different subtypes were identified that during LPS induced inflammation undergo distinct inflammatory transitions with defined transcriptomic profiles64. There is increasing evidence that astrocytes in the brain are heterogeneous in function depending on the context and time of injury and disease, similar to microglia (Figure 2), and that astrocytes interact with microglia and oligodendrocytes to exert immunological functions. Oligodendrocytes As well as the classical innate immune cells, i.e. microglia and astrocytes, oligodendrocytes also contribute to innate immune reactions, expressing receptors and producing immunomodulatory cytokines and chemokines. Originally, oligodendrocytes were regarded as bystanders in immunological responses. However, during CNS insults and disease, oligodendrocytes can aid in protection and regenerative processes, but can also contribute to neurodegeneration through poor production or repair of myelin. Expression of MHC Class I on oligodendrocytes was initially labelled as controversial. However, oligodendrocytes upregulate MHC class I expression after IFN-γ treatment65. Additionally, oligodendrocytes express pattern recognition
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