Lily Keane

Karolinska Institutet

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Bertrand Joseph

Karolinska Institutet

Mathilde Cheray

Karolinska Institutet

Kathleen Grabert

Karolinska Institutet

Lara Frieß

Karolinska Institutet

Patricia González-Rodríguez

Karolinska Institutet

Austėja Balevičiūtė

Karolinska Institutet

Pinelopi Engskog-Vlachos

Karolinska Institutet

Michael T. Heneka

German Center for Neurodegenerative Diseases

Melania Capasso

German Center for Neurodegenerative Diseases

Darío Tejera

University of Bonn

Cooperative Institutions

Karolinska Institutet

German Center for Neurodegenerative Diseases

University College London

Karolinska University Hospital

Universidad de Sevilla

University of Bonn

Queen Mary University of London

Instituto de Biomedicina de Sevilla

Hospital Universitario Virgen del Rocío

Universidad Pablo de Olavide

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Clonal haematopoiesis-associated, age-related motor deficits caused by monocyte-derived microglia

Nature reviews. Immunology (2024)

Austėja Balevičiūtė Lily Keane

Neuropathology

Monocyte

Parenchyma

10.1038/s41577-024-00997-8

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Arg1⁺ microglia are critical for shaping cognition in female mice

bioRxiv (Cold Spring Harbor Laboratory) (2021)

Vassilis Stratoulias Rocío Ruiz Shigeaki Kanatani Ahmed M. Osman José Á. Armengol

Abstract Diversity within microglia, the resident brain immune cells, is reported. Whether microglial subsets constitute different subtypes with intrinsic properties and unique functions has not been fully elucidated. Here, we describe a microglial subtype characterized by the expression of the enzyme Arginase-1, i.e. Arg1 + microglia, which is found predominantly in the cholinergic neuron-rich forebrain region during early postnatal development. Arg1 + microglia are frequently observed in close apposition to neurons and exhibit a distinctive molecular signature reflecting a reactive profile. Arg1 deficiency in microglia results in impaired dendritic spine maturation in the hippocampus where cholinergic neurons project, and cognitive behavioural deficiencies in female mice. Our results expand on microglia diversity and provide insights into distinctive spatiotemporal functions exerted by microglial subtypes.

Forebrain

10.1101/2021.08.15.456225

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Citations (1)

Multifaceted microglia — key players in primary brain tumour heterogeneity

Nature Reviews Neurology (2021)

Lily Keane Mathilde Cheray Klas Blomgren Bertrand Joseph

10.1038/s41582-021-00463-2

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Citations (41)

Pathways Regulating Inflammation in Microglia and Ageing

Lily Keane

Source

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Assessing mRNA translation in mouse adult microglia and bone-marrow-derived macrophages

STAR Protocols (2023)

Ignazio Antignano Lily Keane Melania Capasso

Protein synthesis, or mRNA translation, is the biological process through which genetic information stored in messenger RNAs is encoded into proteins. Here, we present an optimized protocol for assessing the translation rate in mouse adult microglia and cultured bone-marrow-derived macrophages. We describe steps for isolating cells, treating them with a puromycin-analog probe, and fluorescently labeling the puromycylated-polypeptide chains. We then detail their quantification by flow cytometry or with a fluorescent plate reader. For complete details on the use and execution of this protocol, please refer to Keane et al. (2021).

Puromycin

Fluorescent protein

10.1016/j.xpro.2023.102559

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The DNA methyltransferase DNMT3A contributes to autophagy long-term memory

Autophagy (2020)

Patricia González-Rodríguez Mathilde Cheray Jens Füllgrabe Maria Salli Pinelopi Engskog-Vlachos

Macroautophagy/autophagy is a conserved catabolic pathway that targets cytoplasmic components for their degradation and recycling in an autophagosome-dependent lysosomal manner. Under physiological conditions, this process maintains cellular homeostasis. However, autophagy can be stimulated upon different forms of cellular stress, ranging from nutrient starvation to exposure to drugs. Thus, this pathway can be seen as a central component of the integrated and adaptive stress response. Here, we report that even brief induction of autophagy is coupled

Sequestosome 1

DNA methyltransferase

BECN1

10.1080/15548627.2020.1816664

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Citations (28)

Proteome integral solubility alteration high-throughput proteomics assay identifies Collectin-12 as a non-apoptotic microglial caspase-3 substrate

Cell Death and Disease (2023)

Kathleen Grabert Pinelopi Engskog-Vlachos Martin Škandík Guillermo Vázquez-Cabrera Adriana‐Natalia Murgoci

Abstract Caspases are a family of proteins mostly known for their role in the activation of the apoptotic pathway leading to cell death. In the last decade, caspases have been found to fulfill other tasks regulating the cell phenotype independently to cell death. Microglia are the immune cells of the brain responsible for the maintenance of physiological brain functions but can also be involved in disease progression when overactivated. We have previously described non-apoptotic roles of caspase-3 (CASP3) in the regulation of the inflammatory phenotype of microglial cells or pro-tumoral activation in the context of brain tumors. CASP3 can regulate protein functions by cleavage of their target and therefore could have multiple substrates. So far, identification of CASP3 substrates has been performed mostly in apoptotic conditions where CASP3 activity is highly upregulated and these approaches do not have the capacity to uncover CASP3 substrates at the physiological level. In our study, we aim at discovering novel substrates of CASP3 involved in the normal regulation of the cell. We used an unconventional approach by chemically reducing the basal level CASP3-like activity (by DEVD-fmk treatment) coupled to a Mass Spectrometry screen (PISA) to identify proteins with different soluble amounts, and consequently, non-cleaved proteins in microglia cells. PISA assay identified several proteins with significant change in their solubility after DEVD-fmk treatment, including a few already known CASP3 substrates which validated our approach. Among them, we focused on the Collectin-12 (COLEC12 or CL-P1) transmembrane receptor and uncovered a potential role for CASP3 cleavage of COLEC12 in the regulation of the phagocytic capacity of microglial cells. Taken together, these findings suggest a new way to uncover non-apoptotic substrates of CASP3 important for the modulation of microglia cell physiology.

Proteome

10.1038/s41419-023-05714-2

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Citations (6)

Atg7 deficiency in microglia drives an altered transcriptomic profile associated with an impaired neuroinflammatory response

Molecular Brain (2021)

Lara Frieß Mathilde Cheray Lily Keane Kathleen Grabert Bertrand Joseph

Abstract Microglia, resident immunocompetent cells of the central nervous system, can display a range of reaction states and thereby exhibit distinct biological functions across development, adulthood and under disease conditions. Distinct gene expression profiles are reported to define each of these microglial reaction states. Hence, the identification of modulators of selective microglial transcriptomic signature, which have the potential to regulate unique microglial function has gained interest. Here, we report the identification of ATG7 (Autophagy-related 7) as a selective modulator of an NF-κB-dependent transcriptional program controlling the pro-inflammatory response of microglia. We also uncover that microglial Atg7 -deficiency was associated with reduced microglia-mediated neurotoxicity, and thus a loss of biological function associated with the pro-inflammatory microglial reactive state. Further, we show that Atg7 -deficiency in microglia did not impact on their ability to respond to alternative stimulus, such as one driving them towards an anti-inflammatory/tumor supportive phenotype. The identification of distinct regulators, such as Atg7 , controlling specific microglial transcriptional programs could lead to developing novel therapeutic strategies aiming to manipulate selected microglial phenotypes, instead of the whole microglial population with is associated with several pitfalls.

Psychopharmacology

10.1186/s13041-021-00794-7

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Bi-allelic NRXN1α deletion in microglia derived from iPSC of an autistic patient increases interleukin-6 production and impairs supporting function on neuronal networking

Brain Behavior and Immunity (2024)

Raj Bose Mercedes Posada-Pérez Eleni Karvela Martin Škandík Lily Keane

Neuroligin

Neurexin

10.1016/j.bbi.2024.09.001

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Citations (1)