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)
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)
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)
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)
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)
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)
.. if i remember correctly glutamine to glutamate is nevessary for cell shape change in droso mesoderm invagination & cephalic furrow formation too, which is no doubt a similar cell membrane deformation process to phagocytosis
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