Microglia Actively Remodel Adult Hippocampal Neurogenesis through the Phagocytosis Secretome

Díaz-Aparicio, Irune; Paris, Iñaki; Sierra-Torre, Virginia; Plaza-Zabala, Ainhoa; Rodríguez-Iglesias, Noelia; Márquez-Ropero, Mar; Beccari, Sol; Huguet, Paloma; Abiega, Oihane; Alberdi, Elena; Matute, Carlos; Bernales, Irantzu; Schulz, Angela; Otrokocsi, Lilla; Sperlágh, Beáta; Happonen, Kaisa E.; Lemke, Greg; Maletić-Savatić, Mirjana; Valero, Jorge; Sierra, Amanda

doi:10.1523/jneurosci.0993-19.2019

Cited by 232 publications

(225 citation statements)

References 73 publications

(111 reference statements)

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“…Along these lines, monocyte-derived microglia-like cells from individuals with schizophrenia exhibit increased synapse engulfment 56 . Expression of P2Y 12 in microglia is important for synaptic plasticity 57 and for adult hippocampal neurogenesis 58 , which has been associated with the response to antidepressant treatment 59 . Neuronal activity regulates the surveilling function of microglia processes in the cortex via the monoamine neurotransmitter norepinephrine 60 , 61 , which is reduced in the brains of patients with depression 62 , 63 .…”

Section: Discussionmentioning

confidence: 99%

Single-cell mass cytometry of microglia in major depressive disorder reveals a non-inflammatory phenotype with increased homeostatic marker expression

et al. 2020

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Stress-induced disturbances of brain homeostasis and neuroinflammation have been implicated in the pathophysiology of mood disorders. In major depressive disorder (MDD), elevated levels of proinflammatory cytokines and chemokines can be found in peripheral blood, but very little is known about the changes that occur directly in the brain. Microglia are the primary immune effector cells of the central nervous system and exquisitely sensitive to changes in the brain microenvironment. Here, we performed the first single-cell analysis of microglia from four different post-mortem brain regions (frontal lobe, temporal lobe, thalamus, and subventricular zone) of medicated individuals with MDD compared to controls. We found no evidence for the induction of inflammation-associated molecules, such as CD11b, CD45, CCL2, IL-1β, IL-6, TNF, MIP-1β (CCL4), IL-10, and even decreased expression of HLA-DR and CD68 in microglia from MDD cases. In contrast, we detected increased levels of the homeostatic proteins P2Y12 receptor, TMEM119 and CCR5 (CD195) in microglia from all brain regions of individuals with MDD. We also identified enrichment of non-inflammatory CD206hi macrophages in the brains of MDD cases. In sum, our results suggest enhanced homeostatic functions of microglia in MDD.

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Section: Discussionmentioning

confidence: 99%

Single-cell mass cytometry of microglia in major depressive disorder reveals a non-inflammatory phenotype with increased homeostatic marker expression

et al. 2020

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“…Significantly, knockdown of microglial IL4Rα decreased the number of Arg1 + microglia and abrogated the antidepressant effects of IL4 overexpression, suggesting that IL4-driven Arg1 + microglia play a key role in protecting from CMS-induced depression-like behaviors. 26 Microglia constitute a prominent cell population within the hippocampal neurogenic niche 44 . Our results confirmed that CMS resulted in pro-inflammatory activation of microglia and inhibition of hippocampal neurogenesis.…”

Section: Discussionmentioning

confidence: 99%

IL4-driven microglia modulate stress resilience through BDNF-dependent neurogenesis

Zhang

Rong

Zhang

et al. 2020

Preprint

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Running title: IL4-driven microglia modulate neurogenesis and stress resilience In Brief:Zhang et al. show that IL4-induced Arg1 + microglia restore hippocampal neurogenesis and promote resilience against stress in mice by increasing BDNF levels. Targeting microglia with immunomodulatory factors may be a strategy for treating mood disorders.2 Highlights:1. Vulnerability to stress in mice is associated with reduced IL4 signaling in the hippocampus 2. Brain-derived IL4 promotes adult hippocampal neurogenesis and stress resistance by driving Arg1 + microglia 3. IL4-driven Arg1 + microglia enhance hippocampal neurogenesis via a BDNF-dependent pathway 3 Abstract Adult neurogenesis in the dentate gyrus of the hippocampus is regulated by specific groups of microglia and is functionally implicated in behavioral responses to stress. However, the role of microglia in modulating hippocampal neurogenesis in stress responses remains poorly understood. Here we investigated the effects of IL4-driven Arg1 + microglia in the restoration of hippocampal neurogenesis and conferment of stress resilience. We found that low IL4 levels in the hippocampus of mice was associated with greater stress vulnerability and, conversely, overexpression of IL4 in the hippocampus induced a large number of Arg1 + microglia and ameliorated stress-induced depressive-like behaviors. Knockdown of microglial IL4 receptors in the hippocampus of mice exacerbated the stress-induced inflammatory response and abolished the antidepressant effects of IL4 overexpression. Enhancement or inhibition of IL4 signaling in hippocampal microglia modulated neurogenesis, and blockade of neurogenesis abolished the resilience to stress-induced depression. We further show that IL4-activated microglia is associated with upregulation of BDNF levels and neurogenesis. Taken together, our findings suggest that IL4-driven microglia in the hippocampus trigger BDNF-dependent neurogenesis in response to chronic stress, helping protect against depressive-like symptoms. These findings identify the modulation of a specific microglial phenotype as a treatment strategy for mood disorders.

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“…IL4-activated microglial cells promote oligodendrogenesis, whereas IFNγ-activated microglial cells stimulate neurogenesis [156]. Recent evidence shows that phagocytic microglia do not only play a role in passive clearance of apoptotic cells, but also play a central role in controlling adult hippocampal neurogenesis [157]. Chronic depletion of the purinergic receptor P2Y12 and the tyrosine kinases of the TAM family Mer tyrosine kinase (MertK)/Axl in mice impairs adult hippocampal neurogenesis, while the conditional reduced expression of MertK expression transiently increases adult hippocampal neurogenesis [157].…”

Section: Physiological Regulation Of Neurogenesis By Microgliamentioning

confidence: 99%

Role of Microglia in Modulating Adult Neurogenesis in Health and Neurodegeneration

Al‐Onaizi

Al-Khalifah

Qasem

et al. 2020

IJMS

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Microglia are the resident immune cells of the brain, constituting the powerhouse of brain innate immunity. They originate from hematopoietic precursors that infiltrate the developing brain during different stages of embryogenesis, acquiring a phenotype characterized by the presence of dense ramifications. Microglial cells play key roles in maintaining brain homeostasis and regulating brain immune responses. They continuously scan and sense the brain environment to detect any occurring changes. Upon detection of a signal related to physiological or pathological processes, the cells are activated and transform to an amoeboid-like phenotype, mounting adequate responses that range from phagocytosis to secretion of inflammatory and trophic factors. The overwhelming evidence suggests that microglia are crucially implicated in influencing neuronal proliferation and differentiation, as well as synaptic connections, and thereby cognitive and behavioral functions. Here, we review the role of microglia in adult neurogenesis under physiological conditions, and how this role is affected in neurodegenerative diseases.

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Microglia Actively Remodel Adult Hippocampal Neurogenesis through the Phagocytosis Secretome

Cited by 232 publications

References 73 publications

Single-cell mass cytometry of microglia in major depressive disorder reveals a non-inflammatory phenotype with increased homeostatic marker expression

Single-cell mass cytometry of microglia in major depressive disorder reveals a non-inflammatory phenotype with increased homeostatic marker expression

IL4-driven microglia modulate stress resilience through BDNF-dependent neurogenesis

Role of Microglia in Modulating Adult Neurogenesis in Health and Neurodegeneration

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