Altered microglial phagocytosis in GPR34‐deficient mice

Preissler, Julia; Grosche, Antje; Lede, Vera; Duc, Diana Le; Krügel, Katja; Matyash, Vitali; Szulzewsky, Frank; Kallendrusch, Sonja; Immig, Kerstin; Kettenmann, Helmut; Bechmann, Ingo; Schöneberg, Torsten; Schulz, Angela

doi:10.1002/glia.22744

Cited by 64 publications

(45 citation statements)

References 57 publications

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“…Our previous results showed that GPR34 deficiency leads to an altered function of the innate immune system (11). The employed bioinformatics approach revealed a role in the acquired Igmediated immune response (Table I), which is in agreement with a previous study (6).…”

Section: Discussionsupporting

confidence: 91%

“…GPR34 belongs to the P2Y 12 -like receptor group, and its expression levels have been related to impaired immunity (6,11) and development of lymphoma and gastric cancer (35)(36)(37)(38). Upregulation of the receptor has also been linked to neuroinflammation (9).…”

Section: Discussionmentioning

confidence: 99%

“…The functional modules suggested an involvement of the acquired immune system, but previous studies showed GPR34 absence leads to altered innate immune functions, such as phagocytosis (11). DCs are an important subset of the spleen cell populations (27) and they constitute the link between innate and adaptive immune responses.…”

Section: Identification Of Gpr34-related Functional Modulesmentioning

confidence: 99%

“…Immune systemchallenging conditions on mice showed that GPR34 deficiency results in an improper immune response, with higher susceptibility to systemic infections (6). This is most probably due to altered phagocytosis in GPR34-deficient mice (11). Despite clear identification of the transcriptional starts in both the rodent and human GPR34 genes, in vitro attempts to identify the promoter and characterize its regulation were unsuccessful (10).…”

mentioning

confidence: 99%

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Dendritic Cells Regulate GPR34 through Mitogenic Signals and Undergo Apoptosis in Its Absence

Jäger

Schulz

Lede

et al. 2016

The Journal of Immunology

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Dendritic cells (DCs) are specifically equipped with the G protein–coupled receptor 34 (GPR34). Tight regulation of GPR34 gene expression seems highly important for proper immunological functions, because the absence of this receptor leads to an alteration of the immune response, whereas overexpression was reported to be involved in neuroinflammation. However, the regulatory mechanism of GPR34 expression has not yet been investigated. Whole-transcriptome RNA sequencing analysis from spleens and DCs of GPR34 knockout and wild-type mice, combined with protein–protein interaction data, revealed functional modules affected by the absence of this receptor. Among these, NF-κB, MAPK, and apoptosis-signaling pathways showed high significance. Using murine DCs we experimentally show that NF-κB and MAPK pathways are involved in the downregulation of GPR34. DCs lacking GPR34 have a higher caspase-3/7 activity and increased apoptosis levels. Our study reveals a novel role of GPR34 in the fate of DCs and identifies a regulatory mechanism that could be relevant for treatment of GPR34-overexpressing pathologies, such as neuroinflammatory or cancer conditions.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Identification Of Gpr34-related Functional Modulesmentioning

confidence: 99%

mentioning

confidence: 99%

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Dendritic Cells Regulate GPR34 through Mitogenic Signals and Undergo Apoptosis in Its Absence

Jäger

Schulz

Lede

et al. 2016

The Journal of Immunology

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“…GPR34 knockout microglia showed impaired phagocytosis of cryptococcal cells. 85 Studies with complement deficient animals indicate that the complement system plays a critical role in resistance to cryptococcosis. 86,87 The complement system is an important regulator of the inflammatory response against C. neoformans and contributes to host resistance by opsonization of the yeast to facilitate adhesion and phagocytosis by peripheral phagocytic cells.…”

Section: Opportunistic Fungal Infectionsmentioning

confidence: 99%

Role of microglia in fungal infections of the central nervous system

2016

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Most fungi are capable of disseminating into the central nervous system (CNS) commonly being observed in immunocompromised hosts. Microglia play a critical role in responding to these infections regulating inflammatory processes proficient at controlling CNS colonization by these eukaryotic microorganisms. Nonetheless, it is this inflammatory state that paradoxically yields cerebral mycotic meningoencephalitis and abscess formation. As peripheral macrophages and fungi have been investigated aiding our understanding of peripheral disease, ascertaining the key interactions between fungi and microglia may uncover greater abilities to treat invasive fungal infections of the brain. Here, we present the current knowledge of microglial physiology. Due to the existing literature, we have described to greater extent the opportunistic mycotic interactions with these surveillance cells of the CNS, highlighting the need for greater efforts to study other cerebral fungal infections such as those caused by geographically restricted dimorphic and rare fungi.

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Phospholipid localization implies microglial morphology and function via Cdc42 in vitro

Tokizane

Konishi

Makide

et al. 2017

Glia

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Under a quiescent state, microglia exhibit a ramified shape, rather than the amoeboid-like morphology following injury or inflammation. The manipulation of microglial morphology in vitro has not been very successful, which has impeded the progress of microglial studies. We demonstrate that lysophosphatidylserine (LysoPS), a kind of lysophospholipids, rapidly and substantially alters the morphology of primary cultured microglia to an in vivo-like ramified shape in a receptor independent manner. This mechanism is mediated by Cdc42 activity. LysoPS is incorporated into the plasma membrane and converted to phosphatidylserine (PS) via the Lands' cycle. The accumulated PS on the membrane recruits Cdc42. Both Cdc42 and PS colocalize predominantly in primary and secondary processes, but not in peripheral branches or tips of microglia. Along with the morphological changes LysoPS suppresses inflammatory cytokine production and NF-kB activity. The present study provides a tool to manipulate a microglial phenotype from an amoeboid to a fully ramified in vitro, which certainly contributes to studies exploring microglial physiology and pathology.

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Altered microglial phagocytosis in GPR34‐deficient mice

Cited by 64 publications

References 57 publications

Dendritic Cells Regulate GPR34 through Mitogenic Signals and Undergo Apoptosis in Its Absence

Dendritic Cells Regulate GPR34 through Mitogenic Signals and Undergo Apoptosis in Its Absence

Role of microglia in fungal infections of the central nervous system

Phospholipid localization implies microglial morphology and function via Cdc42 in vitro

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