roisinmcmanus.bsky.social
Group Leader @DZNE Bonn and @Institute of Innate Immunity 🇩🇪, PhD @TCD 🇮🇪
Neuroimmunologist, we study innate immune signalling, inflammasomes and immunometabolism in aging and dementia ðŸ§
https://www.iiibonn.de/roisin-mcmanus-lab/roisin-mcmanus-lab-science
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475 following
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📧 Do contact me directly if you have any questions about this role or our work: [email protected]
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📧 Do contact me directly if you have any questions about this role or our work: [email protected]
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Thanks to @dzne.science @immunosens.bsky.social @alzassociation.bsky.social @jpnd @dfg.de @sfb1454.bsky.social for supporting our research!
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This work is possible due to generous support from @dfg.de @sfb1454.bsky.social @immunosens.bsky.social @alzassociation.bsky.social @jpnd @dzne.science
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This follows on from our recent finding that #NLRP3 controls how #microglia use glutamine generating specific metabolites that modulate cell activity, therefore we set out to summarise the latest research on microglial immunometabolism from the last 2 years ðŸ§
pubmed.ncbi.nlm.nih.gov/39904338/
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Oh I’m not going this year 🙈 have another appointment. Hope we can catch up soon!
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Thank you Steph! Looking forward to seeing what other tricks NLRP3 has up its sleeves 🥼🧠delighted you’ve taken this on 💪
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Thanks Rebecca 🤗
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This work highlights #NLRP3 inhibition as an important therapeutic target in #dementia, by not only blocking inflammation but also reprogramming the cells on a metabolic and epigenetic level (18)
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We then tested a NLRP3 inhibitor that could cross into the brain. NLRP3 inhibition reduced inflammasome activation and reprogrammed microglia to increase Abeta uptake, which was driven by SLC1A3+ microglia (17)
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In contrast, inhibiting JMJD3 reduced Slc1a3 mRNA, and the NLRP3-/- microglia were no longer metabolically efficient nor could they phagocytosis Abeta. aKG could not rescue this effect, confirming it was acting on the same part of the pathway (16)
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aKG is also an important co-factor for enzymes that modify the epigenetic landscape e.g. JMJD3. In line with this, we found the Slc1a3 gene region was more open and active in NLRP3-/- microglia (15)
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NLRP3 inhibition could mimic the genetic knock out, but only when used over many days. Interestingly the inhibitor-induced metabolic changes including increased aKG occurred upstream of gene transcription and phagocytic changes (14)
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In the scRNAseq, metabolism and phagocytosis were connected. Functionally the increased phagocytosis in the NLRP3-/- microglia was lost, when cells were deprived of glutamine or glutamate (via SLC1A3 inhibition). However aKG could rescue this (13)
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By tracing glutamine utilisation, we observed that NLRP3-/- cells preferred to use glutamine to produce the metabolite alpha-ketoglutarate (aKG) and the concentration of aKG (downstream of glutamate) was also increased (12)
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At a functional level, NLRP3-/- microglia had increased mitochondrial activity and respiration (oxygen consumption rate – OCR) (11)
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In contrast, in post mortem brain tissue of those with #Alzheimer’s disease who have inflammasome activation in their brain, we found reduced levels of SLC1A3 which was expressed in both microglia and astrocytes (10)
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At a protein level, we observed that microglia express SLC1A3 intracellularly, and the amount was increased in NLRP3-/- cells and cortex (9)
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SLC1A3 is well characterised on astrocytes. To verify the expression changes we performed bulk RNAseq on different NLRP3-/- microglia ex vivo and again saw an increase in microglial Slc1a3 (8)
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To uncover what was driving this, we did single cell RNAseq. This unveiled a population of NLRP3-/- microglia with a strong metabolic and phagocytic signature, and the most significantly changed gene was the glutamate transporter Slc1a3 (7)
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A thread on our main findings:
During my postdoc I noticed something surprising, where NLRP3-/- microglia were much better at #phagocytosis than wild-type cells even under basal (unstimulated) conditions (6)
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If you’re curious whether this mechanism is relevant for other pathways or cell function, stay tuned for our next story from the McManus lab that we will be submitting soon! (5)
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From my side this work would not have been possible without generous support from @afi-ev.bsky.social, @immunosens.bsky.social , @sfb1454.bsky.social @dfg.de and the @alzassociation.bsky.social (4)
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Thanks to the reviewers and editors @cellpress.bsky.social for their insightful comments and helpful suggestions (3)