Microglia and monocytes in inflammatory CNS disease: integrating phenotype and function

Abstract

In neurological diseases, the actions of microglia, the resident myeloid cells of the CNS parenchyma, may diverge from, or intersect with, those of recruited monocytes to drive immune-mediated pathology. However, defining the precise roles of each cell type has historically been impeded by the lack of discriminating markers and experimental systems capable of accurately identifying them. Our ability to distinguish microglia from monocytes in neuroinflammation has advanced with single-cell technologies, new markers and drugs that identify and deplete them, respectively. Nevertheless, the focus of individual studies on particular cell types, diseases or experimental approaches has limited our ability to connect phenotype and function more widely and across diverse CNS pathologies. Here, we critically review, tabulate and integrate the disease-specific functions and immune profiles of microglia and monocytes to provide a comprehensive atlas of myeloid responses in viral encephalitis, demyelination, neurodegeneration and ischemic injury. In emphasizing the differential roles of microglia and monocytes in the severe neuroinflammatory disease of viral encephalitis, we connect inflammatory pathways common to equally incapacitating diseases with less severe inflammation. We examine these findings in the context of human studies and highlight the benefits and inherent limitations of animal models that may impede or facilitate clinical translation. This enables us to highlight common and contrasting, non-redundant and often opposing roles of microglia and monocytes in disease that could be targeted therapeutically.

Mechanistic Studies of Gypenosides in Microglial State Transition and its Implications in Depression-Like Behaviors: Role of TLR4/MyD88/NF-κB Signaling

“…For example, a number of studies have found that pro-inflammatory microglial phenotypes secrete proinflammatory cytokines consisting of tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6, and iNOS, which lead to dysfunction of the neurotrophic system (Park et al, 2015;Zusso et al, 2019). In contrast, a neuroprotective microglial phenotype, contributes to antagonizing inflammation-induced damage by enhancing the expression of different mediators, such as IL-10 and TGF-β (Li et al, 2021;Spiteri et al, 2022). In addition, the dark microglia, a recently described phenotype rarely observed in the brain under steady state conditions, becomes abundant during nonhomeostatic conditions such as chronic stress, aging, and so on (Bisht et al, 2016;Stratoulias et al, 2019).…”

Molecular Mechanisms in the Genesis of Seizures and Epilepsy Associated With Viral Infection

“…However, the specific role of microglia and other CNS resident cells in this process and their interactions with CNS infiltrating immune cells, such as blood-borne monocytes and T cells, are only incompletely understood. At least in part, this is due to the problems of differentiating invading monocytes from activated microglia in the brain and the lack of selective tools to manipulate these two types of myeloid cells ( Greter et al, 2015 ; Butovsky and Weiner, 2018 ; Spiteri et al, 2022 ). Because of the BBB, peripheral monocytes are not found in the CNS parenchyma unless there is overt damage to the barrier or unless pathogen-induced chemokine responses in the brain parenchyma are sufficient to drive monocyte infiltration across the barrier.…”

Comparing the potential of microglia preparations generated using different human iPSC-based differentiation methods to model microglia-mediated mechanisms of amyotrophic lateral sclerosis pathophysiology

“…Activated microglia also release inflammatory cytokines that can promote astrocyte activation and be toxic to neighbouring neurons. The balanced contributions of resting and activated microglia mediate both beneficial (protective) and detrimental (inflammatory) effects on the surrounding cells, depending on the specific context (reviewed by Prinz et al ., 2019; Miron & Priller, 2020; Mendes & Majewska, 2021; Spiteri et al ., 2022).…”