Microglia responses to interleukin‐6 and type I interferons in neuroinflammatory disease

Abstract

Microglia are the resident macrophages of the central nervous system (CNS). They are a heterogenous, exquisitely responsive, and highly plastic cell population, which enables them to perform diverse roles. They sense and respond to the local production of many different signals, including an assorted range of cytokines. Microglia respond strongly to interleukin‐6 (IL‐6) and members of the type I interferon (IFN‐I) family, IFN‐alpha (IFN‐α), and IFN‐beta (IFN‐β). Although these cytokines are essential in maintaining homeostasis and for activating and regulating immune responses, their chronic production has been linked to the development of distinct human neurological diseases, termed “cerebral cytokinopathies.” IL‐6 and IFN‐α have been identified as key mediators in the pathogenesis of neuroinflammatory disorders including neuromyelitis optica and Aicardi‐Goutières syndrome, respectively, whereas IFN‐β has an emerging role as a causal factor in age‐associated cognitive decline. One of the key features that unites these diseases is the presence of highly reactive microglia. The current understanding is that microglia contribute to the development of cerebral cytokinopathies and represent an important therapeutic target. However, it remains to be resolved whether microglia have beneficial or detrimental effects. Here we review and discuss what is currently known about the microglial response to IL‐6 and IFN‐I, based on both animal models and clinical studies. Foundational knowledge regarding the microglial response to IL‐6 and IFN‐I is now being used to devise therapeutic strategies to ameliorate neuroinflammation and promote repair: either through targeting microglia, or by targeting the reduction of CNS levels or downstream biological pathways of IL‐6 or IFN‐I.

Astrocyte–Oligodendrocyte–Microglia Crosstalk in Astrocytopathies

“…In agreement, a review by West et al (2019) explained the strong response of microglia in the context of sustained and elevated levels of IFNα (West et al, 2019). This strong response is characterized by a hypertrophied phenotype (West et al, 2019) and increased expression of several IFNstimulated genes and the nuclear transcription factor IRF1 as well as a cell-surface molecule CD68 (a T-lymphocyte attractor) (Li W. et al, 2018). Although not markedly present, in the autopsy case described by Klok et al (2015), CD68 + microglia and CD3 + lymphocytes were noted (Klok et al, 2015).…”

“…Sase et al (2018) proposed that microglia in the AGS brain might be activated by astrocytemediated production of type I IFNs or in a cell autonomous fashion (Sase et al, 2018). In agreement, a review by West et al (2019) explained the strong response of microglia in the context of sustained and elevated levels of IFNα (West et al, 2019). This strong response is characterized by a hypertrophied phenotype (West et al, 2019) and increased expression of several IFNstimulated genes and the nuclear transcription factor IRF1 as well as a cell-surface molecule CD68 (a T-lymphocyte attractor) (Li W. et al, 2018).…”

The BXD21/TyJ recombinant inbred strain as a model for innate inflammatory response in distinct brain regions

“…In addition, it has been established that microglia respond to IL-6 among other kind of cytokines. Microglia are capable of producing and reacting to the immune system via responsiveness to cytokines and their autoregulation 47 . Here, we have seen that the cerebellum, hippocampus and striatum are susceptible to cytokines in BXD21/TyJ RI.…”

Molecular and cellular mechanisms of central nervous system alteration in COVID-19

“…Уровни провоспалительных цитокинов, таких как IL-1b, IL-6, IL-8 и TNFa, и их соотношение с противовоспалительными цитокинами, такими как IL-Ra и IL-10, коррелируют с прогрессированием повреждения при многих воспалительных заболеваниях ЦНС, включая оптический нейромиелит, острый диссеминированный энцефаломиелит, боковой амиотрофический склероз, энцефалит, болезнь Паркинсона, черепно-мозговые травмы, эпилепсию и инсульт [88].…”