The Role of TGFβ Signaling in Microglia Maturation and Activation

Spittau, Björn; Dokalis, Nikolaos; Prinz, Marco

doi:10.1016/j.it.2020.07.003

Cited by 68 publications

(38 citation statements)

References 103 publications

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“…The Tnf/Ifng axis is the major pro-inflammatory cytokine signaling in neuroinflammation. Tgfb1-Mapk-Apoe axis can maintain homeostasis of macroglia and restrain pro-inflammatory activation of microglia [78]. Thus, the upstream regulation network of Trem2-dependent DAM is a complex composed of both pro-and anti-inflammatory signaling pathways (Table 1).…”

Section: Ank Hif1a Tgfb1mentioning

confidence: 99%

TREM2 Mediates Microglial Anti-Inflammatory Activations in Alzheimer’s Disease: Lessons Learned from Transcriptomics

Xue

2021

Cells

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Alzheimer’s disease (AD) is a lethal neurodegenerative disorder primarily affecting the aged population. The etiopathogenesis of AD, especially that of the sporadic type, remains elusive. The triggering receptor expressed on myeloid cells 2 (TREM2), a member of TREM immunoglobulin superfamily, plays a critical role in microglial physiology. Missense mutations in human TREM2 are determined as genetic risk factors associated with the development of sporadic AD. However, the roles of TREM2 in the pathogenesis of AD are still to be established. In this review, we outlined the influence of Trem2 on balance of pro- and anti-inflammatory microglial activations from a perspective of AD mouse model transcriptomics. On this basis, we further speculated the roles of TREM2 in different stages of AD, which may shed light to the development of TREM2-targeted strategy for the prevention and treatment of this neurodegenerative disorder.

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Section: Ank Hif1a Tgfb1mentioning

confidence: 99%

TREM2 Mediates Microglial Anti-Inflammatory Activations in Alzheimer’s Disease: Lessons Learned from Transcriptomics

Xue

2021

Cells

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“…Therefore, the transcriptional effects observed in the human macrophages correlate with our observation of the morphology changes in the ex vivo slices. Furthermore, TGF-β signaling in microglia is central in the prevention of excessive activation of mature microglia, whereas homeostatic gene expression signature is not affected by TGF-β ( 59 ). Microglial activation is generally considered to be associated with aging.…”

Section: Discussionmentioning

confidence: 99%

CD22 Blockage Restores Age-Related Impairments of Microglia Surveillance Capacity

et al. 2021

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Microglia, the innate immune cells of the brain, are essential for maintaining homeostasis by their ramified, highly motile processes and for orchestrating the immune response to pathological stimuli. They are implicated in several neurodegenerative diseases like Alzheimer’s and Parkinson’s disease. One commonality of these diseases is their strong correlation with aging as the highest risk factor and studying age-related alterations in microglia physiology and associated signaling mechanism is indispensable for a better understanding of age-related pathomechanisms. CD22 has been identified as a modifier of microglia phagocytosis in a recent study, but not much is known about the function of CD22 in microglia. Here we show that CD22 surface levels are upregulated in aged versus adult microglia. Furthermore, in the amyloid mouse model PS2APP, Aβ-containing microglia also exhibit increased CD22 signal. To assess the impact of CD22 blockage on microglia morphology and dynamics, we have established a protocol to image microglia process motility in acutely prepared brain slices from CX3CR1-GFP reporter mice. We observed a significant reduction of microglial ramification and surveillance capacity in brain slices from aged versus adult mice. The age-related decrease in surveillance can be restored by antibody-mediated CD22 blockage in aged mice, whereas surveillance in adult mice is not affected by CD22 inhibition. Moreover to complement the results obtained in mice, we show that human iPSC-derived macrophages exhibit an increased phagocytic capacity upon CD22 blockage. Downstream analysis of antibody-mediated CD22 inhibition revealed an influence on BMP and TGFβ associated gene networks. Our results demonstrate CD22 as a broad age-associated modulator of microglia functionality with potential implications for neurodegenerative disorders.

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“…Immunohistochemistry and transgenic approaches have suggested neuron-derived TGFβ1 and TGFβ2 released by NG2-glia to be critically involved in triggering postnatal microglia maturation [18,23]. Further studies have clearly demonstrated that TGFβ1 is essential for microglia development [24] and maturation [25]. The deletion of TGFβ1 expression in the CNS [17], impairment of extracellular TGFβ1 processing and activation [26,27], or silencing of microglial TGFβ1 signaling by deletion of the TGFβ1 receptor Tgfbr2 [28] resulted in a loss of microglia maturation, characterized by a lack of homeostatic microglia marker expression.…”

Section: Mouse Postnatal Microglia Maturationmentioning

confidence: 99%

Microglia Development and Maturation and Its Implications for Induction of Microglia-Like Cells from Human iPSCs

Wurm

Konttinen

Andressen

et al. 2021

IJMS

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Microglia are resident immune cells of the central nervous system and play critical roles during the development, homeostasis, and pathologies of the brain. Originated from yolk sac erythromyeloid progenitors, microglia immigrate into the embryonic brain parenchyma to undergo final postnatal differentiation and maturation driven by distinct chemokines, cytokines, and growth factors. Among them, TGFβ1 is an important regulator of microglial functions, mediating homeostasis, anti-inflammation, and triggering the expression of microglial homeostatic signature genes. Since microglia studies are mainly based on rodent cells and the isolation of homeostatic microglia from human tissue is challenging, human-induced pluripotent stem cells have been successfully differentiated into microglia-like cells recently. However, employed differentiation protocols strongly vary regarding used cytokines and growth factors, culture conditions, time span, and cell yield. Moreover, the incomplete differentiation of human microglia can hamper the similarity to primary human microglia and dramatically influence the outcome of follow-up studies with these differentiated cells. This review summarizes the current knowledge of the molecular mechanisms driving rodent microglia differentiation in vivo, further compares published differentiation protocols, and highlights the potential of TGFβ as an essential maturation factor.

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The Role of TGFβ Signaling in Microglia Maturation and Activation

Cited by 68 publications

References 103 publications

TREM2 Mediates Microglial Anti-Inflammatory Activations in Alzheimer’s Disease: Lessons Learned from Transcriptomics

TREM2 Mediates Microglial Anti-Inflammatory Activations in Alzheimer’s Disease: Lessons Learned from Transcriptomics

CD22 Blockage Restores Age-Related Impairments of Microglia Surveillance Capacity

Microglia Development and Maturation and Its Implications for Induction of Microglia-Like Cells from Human iPSCs

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