In vivo characterization of functional states of cortical microglia during peripheral inflammation

Riester, Karin Dorota; Brawek, Bianca; Savitska, Daria; Fröhlich, Nicole; Zirdum, Elizabeta; Mojtahedi, Nima; Heneka, Michael T.; Garaschuk, Olga

doi:10.1016/j.bbi.2019.12.007

Cited by 43 publications

(35 citation statements)

References 71 publications

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“…Inflammation can also evoke greater spontaneous microglial calcium signaling and modify how microglia respond to the extracellular environment. When administered peripherally, LPS dramatically increases the proportion of microglia exhibiting spontaneous calcium activity (Pozner et al, 2015; Riester et al, 2020). Increased microglial calcium signaling depends on inflammasome activity (NLRP3), but it is unclear whether this occurs through direct IL‐1β signaling to microglia (a potential endocrine signal to IL‐1R) or a broader heightening of the inflammatory state (Riester et al, 2020).…”

Section: The Emerging Role Of Microglial Calcium Signaling During Shifts In Homeostasismentioning

confidence: 99%

“…increases the proportion of microglia exhibiting spontaneous calcium activity (Pozner et al, 2015;Riester et al, 2020). Increased microglial calcium signaling depends on inflammasome activity (NLRP3), but it is unclear whether this occurs through direct IL-1β signaling to microglia (a potential endocrine signal to IL-1R) or a broader heightening of the inflammatory state (Riester et al, 2020). LPS can also alter how microglia utilize calcium signaling during injury.…”

Section: The First Context For Microglial Calcium Responses: Injury and Inflammationmentioning

confidence: 99%

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How microglia sense and regulate neuronal activity

Umpierre

2020

Glia

125

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Microglia are innate immune cells of the central nervous system that sense extracellular cues. Brain injuries, inflammation, and pathology evoke dynamic structural responses in microglia, altering their morphology and motility. The dynamic motility of microglia is hypothesized to be a critical first step in sensing local alterations and engaging in pattern‐specific responses. Alongside their pathological responses, microglia also sense and regulate neuronal activity. In this review, we consider the extracellular molecules, receptors, and mechanisms that allow microglia to sense neuronal activity changes under both hypoactivity and hyperactivity. We also highlight emerging in vivo evidence that microglia regulate neuronal activity, ranging from physiological to pathophysiological conditions. In addition, we discuss the emerging role of calcium signaling in microglial responses to the extracellular environment. The dynamic function of microglia in monitoring and influencing neuronal activity may be critical for brain homeostasis and circuit modification in health and disease.

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Section: The Emerging Role Of Microglial Calcium Signaling During Shifts In Homeostasismentioning

confidence: 99%

Section: The First Context For Microglial Calcium Responses: Injury and Inflammationmentioning

confidence: 99%

How microglia sense and regulate neuronal activity

Umpierre

2020

Glia

125

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“…These damageinduced Ca 2+ transients were mediated by activation of metabotropic purinergic receptors, which are highly expressed in microglia [46], as well as Ca 2+ release from the intracellular Ca 2+ stores [37]. Subsequent studies substantiated our hypothesis that abundant somatic Ca 2+ transients in microglia reflect pathological alterations in tissue homeostasis, e.g., aging [39,40], laser-induced focal brain injury [47], amyloid pathology [48], or peripheral inflammation [44,47]. Interestingly, the majority of Ca 2+ transients evoked by laser-induced brain injury occurred in the microglial processes only [47].…”

Section: Ca 2+ Signalingmentioning

confidence: 74%

“…Intracellular Ca 2+ signaling is actively involved into both sensor and effector functions of microglia [34,[43][44][45]. Due to technical reasons, however, it has long been challenging to study microglial Ca 2+ signaling in vivo.…”

Section: Ca 2+ Signalingmentioning

confidence: 99%

“…As non-excitable cells, microglia rely on intracellular Ca 2+ signaling to trigger their executive functions, e.g., increased processing and release of pro-inflammatory cytokines like IL-1β, IL-18 [63], TNF-α [64,65], or nitric oxide [66]. The latter might signal in an auto-/paracrine manner to sensitize microglia [34,44,45], which, in turn, might react much more vividly in case of subsequent pathology. Indeed, although basal levels of typical pro-inflammatory cytokines (TNF-α, IL-6, IL-1β) were similar in microglia from young and middle-aged mice, peripheral LPS challenge led to higher expression levels of these cytokines in brains of middle-aged mice [67].…”

Section: Unexpected Alertness Of Middle-age Microgliamentioning

confidence: 99%

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Changing Functional Signatures of Microglia along the Axis of Brain Aging

Brawek

Skok

Garaschuk

2021

IJMS

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Microglia, the innate immune cells of the brain, are commonly perceived as resident macrophages of the central nervous system (CNS). This definition, however, requires further specification, as under healthy homeostatic conditions, neither morphological nor functional properties of microglia mirror those of classical macrophages. Indeed, microglia adapt exceptionally well to their microenvironment, becoming a legitimate member of the cellular brain architecture. The ramified or surveillant microglia in the young adult brain are characterized by specific morphology (small cell body and long, thin motile processes) and physiology (a unique pattern of Ca2+ signaling, responsiveness to various neurotransmitters and hormones, in addition to classic “immune” stimuli). Their numerous physiological functions far exceed and complement their immune capabilities. As the brain ages, the respective changes in the microglial microenvironment impact the functional properties of microglia, triggering further rounds of adaptation. In this review, we discuss the recent data showing how functional properties of microglia adapt to age-related changes in brain parenchyma in a sex-specific manner, with a specific focus on early changes occurring at middle age as well as some strategies counteracting the aging of microglia.

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Plaque vicinity as a hotspot of microglial turnover in a mouse model of Alzheimer's disease

Olmedillas,

Brawek,

et al. 2023

Glia

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Microglia, the major immune cells of the brain, are functionally heterogeneous but in vivo functional properties of these cells are rarely studied at single‐cell resolution. By using microRNA‐9 regulated viral vectors for multicolor labeling and longitudinal in vivo monitoring of individual microglia, we followed their fate in the cortex of healthy adult mice and at the onset of amyloidosis in a mouse model of Alzheimer's disease. In wild‐type mice, microglia were rather mobile (16% of the cells migrated at least once in 10–20 days) but had a low turnover as documented by low division and death rates. Half of the migratory events were tightly associated with blood vessels. Surprisingly, basic migration properties of microglia (i.e., fraction of migrating cells, saltatory migration pattern, speed of migration, translocation distance, and strong association with blood vessels) were preserved in amyloid‐depositing brains, despite amyloid plaques becoming the major destination of migration. Besides, amyloid deposition significantly increased microglial division and death rates. Moreover, the plaque vicinity became a hotspot of microglial turnover, harboring 33% of all migration, 70% of death and 54% of division events.

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In vivo characterization of functional states of cortical microglia during peripheral inflammation

Cited by 43 publications

References 71 publications

How microglia sense and regulate neuronal activity

How microglia sense and regulate neuronal activity

Changing Functional Signatures of Microglia along the Axis of Brain Aging

Plaque vicinity as a hotspot of microglial turnover in a mouse model of Alzheimer's disease

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