Neurofibromatosis 1 - Mutant microglia exhibit sexually-dimorphic cyclic AMP-dependent purinergic defects

Elmadany, Nirmeen; Logiacco, Francesca; Buonfiglioli, Alice; Haage, Verena; Wright-Jin, Elizabeth C.; Schattenberg, Alexander; Papawassiliou, Roxane M.; Kettenmann, Helmut; Semtner, Marcus; Gutmann, David H.

doi:10.1016/j.nbd.2020.105030

Cited by 11 publications

(12 citation statements)

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“…We assume that activation of Hrh1 receptors in astrocytes triggers the release of ATP/ADP which stimulates intracellular Ca 2+ elevations and phagocytic activity in microglia via activation of P2ry12 purinergic receptors. It is well established that these receptors are prominently expressed by microglia and that activation of these receptors can stimulate phagocytosis (Elmadany, Logiacco, et al, 2020; Inoue et al, 2009; Koizumi et al, 2007). In a recent study, we found even a significant decrease in microglia phagocytic activity in the cortex of P91‐P112 male and female WT mice when P2ry12 was blocked.…”

Section: Discussionmentioning

confidence: 99%

Histamine triggers microglial responses indirectly via astrocytes and purinergic signaling

Xia

Logiacco

Huang

et al. 2021

Glia

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Histamine is a monoaminergic neurotransmitter which is released within the entire brain from ascending axons originating in the tuberomammillary nucleus in a sleep state‐dependent fashion. Besides the modulation of neuronal firing patterns, brain histamine levels are also thought to modulate functions of glial cells. Microglia are the innate immune cells and professional phagocytes of the central nervous system, and histamine was previously shown to have multiple effects on microglial functions in health and disease. Isolated microglia respond only to agonists of the Hrh2 subtype of histamine receptors (Hrh), and the expression of that isoform is confirmed by a metadata analysis of microglia transcriptomes. When we studied the effect of the histamine receptor isoforms in cortical and thalamic microglia by in situ live cell Ca2+ imaging using a novel, microglia‐specific indicator mouse line, microglial cells respond to external histamine application mainly in a Hrh1‐, and to a lower extent also in a Hrh2‐dependent manner. The Hrh1 response was sensitive to blockers of purinergic P2ry12 receptors, and since Hrh1 expression was predominantly found in astrocytes, we suggest that the Hrh1 response in microglia is mediated by astrocyte ATP release and activation of P2ry12 receptors in microglia. Histamine also stimulates microglial phagocytic activity via Hrh1‐ and P2ry12‐mediated signaling. Taken together, we provide evidence that histamine acts indirectly on microglial Ca2+ levels and phagocytic activity via astrocyte histamine receptor‐controlled purinergic signaling.

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Section: Discussionmentioning

confidence: 99%

Histamine triggers microglial responses indirectly via astrocytes and purinergic signaling

Xia

Logiacco

Huang

et al. 2021

Glia

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“…Second, to determine whether Nf1 ± microglial functional defects were cell-autonomous, we measured Nf1 ± mice [17,18], YFP-based fluorescence in mice was much weaker; however, detection of process movements was still possible (Additional File 1: Fig. S4A).…”

Section: Microglia Morphology and Function Is Not Altered By Microgli...mentioning

confidence: 99%

“…Process movement in response to injury [17,18,20,27,42] is a P2RY12-mediated function in microglia [13,48]. Microglial membrane current responses following the application of low (10 µM) ATP concentrations largely depend on P2RY12 activation [17,18], which activates K + currents through THIK-1 [3,4,20,42,67].…”

Section: Microglia Morphology and Function Is Not Altered By Microgli...mentioning

confidence: 99%

“…We have previously demonstrated that microglia from mice heterozygous for a germline inactivating mutation in the Neurofibromatosis type 1 (NF1) gene exhibit sexually dimorphic impairments in purinergic function [17,18]. Using in situ analysis of microglia function, we showed that microglia from male, but not female, Nf1 ± mice exhibit impaired phagocytosis, ATP-evoked membrane currents, and lesion-induced process accumulation relative to their wild-type counterparts.…”

Section: Introductionmentioning

confidence: 99%

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Neurofibromatosis type 1-dependent alterations in mouse microglia function are not cell-intrinsic

Logiacco

Grzegorzek

Cordell

et al. 2023

acta neuropathol commun

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We previously discovered a sex-by-genotype defect in microglia function using a heterozygous germline knockout mouse model of Neurofibromatosis type 1 (Nf1 ± mice), in which only microglia from male Nf1 ± mice exhibited defects in purinergic signaling. Herein, we leveraged an unbiased proteomic approach to demonstrate that male, but not female, heterozygous Nf1 ± microglia exhibit differences in protein expression, which largely reflect pathways involved in cytoskeletal organization. In keeping with these predicted defects in cytoskeletal function, only male Nf1 ± microglia had reduced process arborization and surveillance capacity. To determine whether these microglial defects were cell autonomous or reflected adaptive responses to Nf1 heterozygosity in other cells in the brain, we generated conditional microglia Nf1-mutant knockout mice by intercrossing Nf1flox/flox with Cx3cr1-CreER mice (Nf1flox/wt; Cx3cr1-CreER mice, Nf1MG ± mice). Surprisingly, neither male nor female Nf1MG ± mouse microglia had impaired process arborization or surveillance capacity. In contrast, when Nf1 heterozygosity was generated in neurons, astrocytes and oligodendrocytes by intercrossing Nf1flox/flox with hGFAP-Cre mice (Nf1flox/wt; hGFAP-Cre mice, Nf1GFAP ± mice), the microglia defects found in Nf1 ± mice were recapitulated. Collectively, these data reveal that Nf1 ± sexually dimorphic microglia abnormalities are likely not cell-intrinsic properties, but rather reflect a response to Nf1 heterozygosity in other brain cells.

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“… 31 In an NF1 mouse model, male microglia showed a selective decrease in purinergic controlled phagocytosis due to deficits in cyclic adenosine monophosphate regulation. 32 Further work also demonstrates sex as a critical prognostic factor in optic glioma-associated visual decline, as well as neuronal dysfunction, in children with NF1. 33 These studies emphasize both the importance of sexual dimorphism in the CNS immunology, and the uniqueness of CNS immune system compared to the peripheral immune system.…”

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confidence: 95%

Sexual dimorphism of the immune system predicts clinical outcomes in glioblastoma immunotherapy: A systematic review and meta-analysis

Shireman

Ammanuel

Eickhoff

et al. 2022

Neuro-Oncology Advances

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Background Biological differences based on sex have been documented throughout the scientific literature. Glioblastoma (GBM), the most common primary malignant brain tumor in adults, has a male sex incidence bias, however, no clinical trial data examining differential effects of treatment between sexes currently exists. Method We analyzed genomic data, as well as clinical trials, to delineate the effect of sex on the immune system and GBM outcome following immunotherapy. Results We found that in general females possess enriched immunological signatures on gene set enrichment analysis, which also stratified patient survival when delineated by sex. Female GBM patients treated with immunotherapy had a statistically significant survival advantage at the 1-year compared to males (relative risk [RR] = 1.15; P = .0241). This effect was even more pronounced in vaccine-based immunotherapy (RR = 1.29; P = .0158). Conclusions Our study shows a meaningful difference in the immunobiology between males and females that also influences the overall response to immunotherapy in the setting of GBM.

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Neurofibromatosis 1 - Mutant microglia exhibit sexually-dimorphic cyclic AMP-dependent purinergic defects

Cited by 11 publications

References 63 publications

Histamine triggers microglial responses indirectly via astrocytes and purinergic signaling

Histamine triggers microglial responses indirectly via astrocytes and purinergic signaling

Neurofibromatosis type 1-dependent alterations in mouse microglia function are not cell-intrinsic

Sexual dimorphism of the immune system predicts clinical outcomes in glioblastoma immunotherapy: A systematic review and meta-analysis

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