Microglial Interferon Signaling and White Matter

Abstract

Microglia, the resident immune cells of the CNS, are primary regulators of the neuroimmune response to injury. Type I interferons (IFNs), including the IFNαs and IFNβ, are key cytokines in the innate immune system. Their activity is implicated in the regulation of microglial function both during development and in response to neuroinflammation, ischemia, and neurodegeneration. Data from numerous studies in multiple sclerosis (MS) and stroke suggest that type I IFNs can modulate the microglial phenotype, influence the overall neuroimmune milieu, regulate phagocytosis, and affect blood–brain barrier integrity. All of these IFN-induced effects result in numerous downstream consequences on white matter pathology and microglial reactivity. Dysregulation of IFN signaling in mouse models with genetic deficiency in ubiquitin specific protease 18 (USP18) leads to a severe neurological phenotype and neuropathological changes that include white matter microgliosis and pro-inflammatory gene expression in dystrophic microglia. A class of genetic disorders in humans, referred to as pseudo-TORCH syndrome (PTS) for the clinical resemblance to infection-induced TORCH syndrome, also show dysregulation of IFN signaling, which leads to severe neurological developmental disease. In these disorders, the excessive activation of IFN signaling during CNS development results in a destructive interferonopathy with similar induction of microglial dysfunction as seen in USP18 deficient mice. Other recent studies implicate “microgliopathies” more broadly in neurological disorders including Alzheimer’s disease (AD) and MS, suggesting that microglia are a potential therapeutic target for disease prevention and/or treatment, with interferon signaling playing a key role in regulating the microglial phenotype.

Decoding the transcriptional response to ischemic stroke in young and aged mouse brain

“…An outstanding feature of differential response of aged animals to ischemic stroke was upregulation of IFN-I pathway ( Figure 2B, 3A, 5A-E, S2, S3B), which persisted for at least 14 days ( Figure 6E). IFN-Is are antiviral cytokines with pleiotropic roles 129 implicated in a number of CNS pathologies including multiple sclerosis 130,131 , Aicardi-Goutières syndrome, amyotrophic lateral sclerosis 132 , Alzheimer's disease 59,133,134 , spinal cord injury 135 , traumatic brain injury 136,137 and ischemic stroke 100,103,138 . Therefore, we have explored INF-I signaling in more detail and found that two IFN-I regulatory modules are activated by stroke irrespective of age, but only the canonical STATdependent module is differentially activated in aged animals ( Figure 6B-D), likely contributing to an increased neurotoxicity 100 .…”

Molecular Effects of FDA-Approved Multiple Sclerosis Drugs on Glial Cells and Neurons of the Central Nervous System

“…Interferons (IFNs) are naturally occurring cytokines, and their effects on the periphery as well as on the CNS are complex and not completely understood [190,191]. IFNs are known to have major effects on microglia cells, which may cause a cascade of consequences in other CNS cell types [192]. Remarkably, endogenous and exogenously administered IFNs may exert anti-inflammatory [193] as well as pro-inflammatory effects [194][195][196][197] in models for neurodegenerative and non-neurodegenerative diseases.…”

Evidence for genetic correlation between human cerebral white matter microstructure and inflammation

“…Inflammation affects white matter microstructure via elevating levels of circulating pro-inflammatory cytokines, which increase blood-brain barrier permeability (Stolp et al, 2009;Stolp, Dziegielewska, Ek, Potter, & Saunders, 2005;Varatharaj & Galea, 2017) and can trigger inflammatory processes in the brain (Konsman, Parnet, & Dantzer, 2002). Subsequent neuroinflammation has cascading effects that activate microglia (Sankowski, Mader, & Valdés-Ferrer, 2015), which contribute to white matter pathology in the form of volume reductions and loss of oligodendrocyte precursor cells (Li et al, 2017;McDonough, Lee, & Weinstein, 2017;Stolp et al, 2009). Local white matter damage can, in turn, send cytokine-mediated signals back to the periphery (Chen, Castro, Chow, & Reichlin, 1997;Chen & Reichlin, 1998;Romero, Kakucska, Lechan, & Reichlin, 1996), resulting in a reciprocal relationship between white matter microstructure and immune responses.…”