Neuroinflammation: From Molecular Basis to Therapy

Dear Colleagues,

Inflammatory conditions within the central nervous system (CNS) may damage neurons and are generally recognized in the pathogenesis of neuroimmune disorders like acquired demyelinating syndromes and autoimmune encephalopathies. Mounting evidence indicates that neuroinflammation also plays a crucial role in the pathogenesis of several neurodegenerative disorders, such as Parkinson’s (PD), Alzheimer’s (AD), and Huntington’s (HD) diseases, frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS) in addition to acute or chronic infections with CNS involvement, such as HIV infection even under efficient combination antiretroviral therapy (cART), or the recent SARS-CoV-2 infection. Neuroinflammation may indeed be triggered by various stimuli, like infections, traumatic injuries, release of toxic metabolites, abnormal accumulation of proteins or autoimmunity, and is mediated by cytokines, chemokines, and reactive oxygen species (ROS) released by both resident and peripheral cells. While in neuroimmune disorders, like multiple sclerosis, neuroinflammation is driven by blood-derived lymphocytes and monocytes infiltrating the CNS through a disrupted blood–brain barrier, resident reactive glial cells, particularly microglia, are mainly involved in neurodegenerative disorders. Microglia are involved in immune surveillance in the CNS and, when activated, may counteract injuries with a brief and controlled inflammatory response, but their dysfunctional activation may lead to uncontrolled inflammation with continuous release of pro-inflammatory mediators and even recruitment of peripheral immune cells. Microglia senescence may also affect progression of neurodegeneration. While reactive microglia may provide both pro- and anti-inflammatory functions, senescent dystrophic microglia are characterized by reduced motility and phagocytosis, increased ROS production, and a pro-inflammatory state, and could have a significant impact on neuron viability. Reactive microglia are frequently found in brain autopsies of patients suffering from numerous neurodegenerative disorders; however, microglia activation seems nonspecific, and for this reason, neuroinflammation has long been regarded as a secondary effect of neuronal dysfunction or death. Nonetheless, genetics strictly links neuroinflammation and neurodegeneration. In recent years, several genetic variants have been associated to or have been defined as risk factors for neurodegenerative disorders. Variants in TREM2 (triggering receptor expressed on myeloid cells 2), a gene expressed only in microglia, have been associated with AD and FTD. APOE (apolipoprotein E) allele Ɛ4 is the main risk factor for AD: like TREM2, APOE is highly expressed in reactive microglia and TREM2 is involved in the APOE signaling pathway. Variants in PGRN (progranulin), TBK1 (TANK-binding kinase 1), and C9orf72 genes, expressed in the microglia and involved in innate immunity and inflammation, are associated with FTD and ALS. Variants in the LRRK2 (leucine-rich repeat kinase 2) gene are found in patients with PD and immunological disorders, in which this gene is highly expressed in activated microglia and peripheral blood cells and is also involved in innate immunity and inflammation. Understanding the molecular mechanisms of neuroinflammation will be crucial to develop new therapeutic approaches of disorders that affect the CNS.

With this Special Issue, we aim to provide a more comprehensive overview of the role of neuroinflammation. Hence, we are inviting researchers to contribute original research articles and reviews exploring the molecular basis of neuroinflammation in CNS disorders of any kind, from classical neuroimmune disorders to neurodegenerative disorders and neuroinflammatory conditions linked to infectious diseases like HIV and SARS-CoV-2 infections. Contributions from all research areas, including disease modeling, human neuropathology, biochemical, molecular, and clinical studies, genomics, proteomics, or therapeutic interventions are welcome.

Dr. Isabella Zanella
Guest Editor

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