Eomes + Th cells were also found at high levels in the CNS of brain autopsy samples from SPMS. Furthermore, Eomes + Th cells are increased in the peripheral blood and cerebrospinal fluid (CSF) of SPMS patients where the level of these cells was associated with actively progressing disease and so acted as a biomarker to predict SPMS patients at risk of developing worsening disease. We have previously demonstrated that a unique population of T helper cells expressing Eomes (Eomes + Th cells) are expanded in the CNS in a mouse model of SPMS, late, chronic EAE. Immune responses were not previously though to contribute to SPMS pathogenesis however there is growing evidence of an important role for active immune functions in SPMS. SPMS presents with progressive symptoms of brain atrophy, higher brain dysfunction, gait disturbance, and cognitive disorder and develops in MS patients following a period of times with an acute type of disease, relapsing remitting MS (RRMS). However, the pathogenic features of such microglial subsets remain undetermined, as the enhanced IFN-I signature and upregulated MHC II expression in themselves do not have any explicable relevance to neurodegeneration. In addition to DAM, two microglial subsets with high expression of MHC-II and IFN-I-induced genes are highlighted in neurodegeneration, and these microglia may precede the final differentiation of DAM and could help unravel the pathogenic characteristics of microglia. Recent single cell-RNA seq-based analyses point out that the context-dependent heterogeneity of microglia during neurodegeneration and disease-associated microglia (DAM), a microglial subset with highly pathogenic properties, has attracted attention in a mouse model of AD. Due to the broad range of tasks linked to CNS homeostasis, microglia are extremely sensitive to pathological fluctuations in the CNS. In addition, microglia are essential for the maintenance of brain architecture by clearing damaged neurons and pruning synapses during brain development. These cells are involved in the active defense of the central nervous system (CNS) under physiological conditions by responding to and eliminating exogenous insults. Microglia are neuro glia cells that function as resident macrophages in the CNS and form more than 10% of brain cellularity. Recently, glial cells have been revealed as an intrinsic component in neurodegeneration, leading to acceptance as a possible cause or trigger of neuronal cell death, thereby establishing a non-cell autonomous hypothesis of neurodegeneration. Mechanisms discerned from both human and animal studies of neurodegeneration are at best speculative and retrospective, thus yielding no possible prospect of therapeutic intervention. Despite much research, the authentic causes of neurodegeneration are still undetermined. Genetic approaches have identified a number of target molecules related to protein misfolding/aggregation, impaired RNA metabolism, mitochondrial dysfunction, dysregulated epigenetics, etc. Intriguingly, neurodegeneration not only occurs in typical neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and Alzheimer’s disease (AD) but also in chronic neuroinflammatory diseases including secondary progressive multiple sclerosis (SPMS). Neurodegeneration is the status/process of neuronal cell death or the functional breakdown of neuronal cells as part of the progressive failure of the nervous system in neurodegenerative diseases. Collectively, our data highlight a critical contribution of new microglia subsets as a neuroinflammatory hub in immune-mediated neurodegeneration. Interestingly, administration of an L1 inhibitor significantly ameliorated neurodegenerative symptoms of EAE concomitant with reduced accumulation of Eomes + Th cells in the CNS. Furthermore, ORF1, an L1-encoded protein aberrantly expressed in the diseased central nervous system (CNS), stimulated Eomes + Th cells after Trem2-dependent ingestion and presentation in MHC-II context by microglia. Microglia acquire IFN-signature after sensing ectopically expressed long interspersed nuclear element-1 (L1) gene. We demonstrate here that these microglial subsets play intrinsic roles in orchestrating neurotoxic properties of neurotoxic Eomes + Th cells under the neurodegeneration-associated phase of experimental autoimmune encephalomyelitis (EAE) that corresponds to progressive multiple sclerosis (MS). However, the significance of such MHC-II and IFN-I signatures remains elusive. In addition to disease-associated microglia (DAM), microglia with MHC-II and/or IFN-I signatures may form additional pathogenic subsets that are relevant to neurodegeneration.
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