Microglial activation elicits a negative affective state through prostaglandin-mediated modulation of striatal neurons

Klawonn, Anna M.; Fritz, Michael E.; Castany, Sílvia; Pignatelli, Marco; Canal, Carla; Similä, Fredrik; Tejeda, Hugo A.; Levinsson, Julia; Jaarola, Maarit; Jakobsson, Johan; Hidalgo, Juan; Heilig, Markus; Bonci, Antonello; Engblom, David

doi:10.1016/j.immuni.2020.12.016

Cited by 110 publications

(90 citation statements)

References 65 publications

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“…We observed variation within experimental groups throughout our work, which was independent from injection method, capsid variants, Cre-dependent genomes or animal sex. These variations appear in other studies, yet without further discussion of the source of the variation 56,57 .…”

Section: Variability Of Microglial Transduction Efficiencymentioning

confidence: 56%

Optimizing AAV2/6 microglial targeting identified enhanced efficiency in the photoreceptor degenerative environment

Maes

Wögenstein

Colombo

et al. 2021

Preprint

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Adeno-associated viruses (AAVs) are widely used to deliver genetic material in vivo to distinct cell types such as neurons or glial cells allowing for targeted manipulation. Transduction of microglia is mostly excluded from this strategy likely due to the cells' heterogeneous state upon environmental changes, which makes AAV design challenging. Here, we established the retina as a model system for microglial AAV validation and optimization. First, we show that AAV2/6 transduced microglia in both synaptic layers, where layer preference corresponds to the intravitreal or subretinal delivery method. Surprisingly, we observed significantly enhanced microglial transduction during photoreceptor degeneration. Thus, we modified the AAV6 capsid to reduce heparin binding resulting in increased microglial transduction in the outer plexiform layer. Finally, to improve microglial-specific transduction, we validated a Cre-dependent transgene delivery cassette. Together, our results provide a foundation for future studies optimizing AAV-mediated microglia transduction and highlight that environmental conditions influence microglial transduction efficiency.

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Section: Variability Of Microglial Transduction Efficiencymentioning

confidence: 56%

Optimizing AAV2/6 microglial targeting identified enhanced efficiency in the photoreceptor degenerative environment

Maes

Wögenstein

Colombo

et al. 2021

Preprint

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“…This effect was dependent on microglia activation after LPS injection. This inflammation-induced behavior depends on IL-6 signaling acting in an autocrine way in microglia and microglial prostaglandin signaling acting on striatal medium spiny neurons [ 134 ].…”

Section: Molecular Mechanisms Of Neuronal Toxicity In Saementioning

confidence: 99%

Neuroinflammation in Sepsis: Molecular Pathways of Microglia Activation

et al. 2021

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Frequently underestimated, encephalopathy or delirium are common neurological manifestations associated with sepsis. Brain dysfunction occurs in up to 80% of cases and is directly associated with increased mortality and long-term neurocognitive consequences. Although the central nervous system (CNS) has been classically viewed as an immune-privileged system, neuroinflammation is emerging as a central mechanism of brain dysfunction in sepsis. Microglial cells are major players in this setting. Here, we aimed to discuss the current knowledge on how the brain is affected by peripheral immune activation in sepsis and the role of microglia in these processes. This review focused on the molecular pathways of microglial activity in sepsis, its regulatory mechanisms, and their interaction with other CNS cells, especially with neuronal cells and circuits.

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“…Indeed, it is now well-established that these cells are involved in processes as diverse as surfactant degradation and lung alveolar homeostasis, 174,175 electrical conduction in the heart, 176 gastro-intestinal viability and motility, 177 and neuronal development, homeostasis, and excitability. [178][179][180] Indeed, it has been proposed that macrophages engage in mutually beneficial interactions with their niches. 130,154 According to this concept, macrophages control homeostasis of their niche through feedback mechanisms, akin to those described for macrophages and fibroblasts by Medzhitov and colleagues.…”

Section: Feedback Mechanis Msmentioning

confidence: 99%

“…Their pleiotropic alterations suggest that macrophages are crucial for the proper development and function of many cellular microenvironments. Indeed, it is now well‐established that these cells are involved in processes as diverse as surfactant degradation and lung alveolar homeostasis, 174,175 electrical conduction in the heart, 176 gastro‐intestinal viability and motility, 177 and neuronal development, homeostasis, and excitability 178‐180 …”

Section: Feedback Mechanismsmentioning

confidence: 99%

Macrophage‐fibroblast circuits in the spleen

Bellomo

Gentek

Golub

et al. 2021

Immunological Reviews

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Located in the abdominal cavity between the diaphragm and the fundus of the stomach, the spleen is the largest secondary lymphoid organ in the body. It acts mainly as a blood filter that selectively removes immune complexes, circulating pathogens and senescent, dysfunctional, or infected red blood cells. 1 As a result, splenectomy is associated with an increased susceptibility to severe bacterial infections (Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis…) and a major risk of overwhelming sepsis. 2,3 Besides its immune function, the spleen is involved in other important physiological processes such as iron homeostasis. Senescent or ruptured red blood cells are trapped in the spleen and their hemoglobin content is metabolized into free iron, which supplies most of the iron needed for erythropoiesis. 4,5 The adult spleen is also a prominent site for extramedullary hematopoiesis. In conditions of infection, anemia and genetic blood disorders or during pregnancy, hematopoietic stem cells (HSC) mobilized from the bone marrow

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Microglial activation elicits a negative affective state through prostaglandin-mediated modulation of striatal neurons

Cited by 110 publications

References 65 publications

Optimizing AAV2/6 microglial targeting identified enhanced efficiency in the photoreceptor degenerative environment

Optimizing AAV2/6 microglial targeting identified enhanced efficiency in the photoreceptor degenerative environment

Neuroinflammation in Sepsis: Molecular Pathways of Microglia Activation

Macrophage‐fibroblast circuits in the spleen

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