TREM2 regulates purinergic receptor-mediated calcium signaling and motility in human iPSC-derived microglia

• Published in: eLife Vol. 11
• Main Authors: Jairaman, Amit, McQuade, Amanda, Granzotto, Alberto, Kang, You Jung, Chadarevian, Jean Paul, Gandhi, Sunil, Parker, Ian, Smith, Ian, Cho, Hansang, Sensi, Stefano L, Othy, Shivashankar, Blurton-Jones, Mathew, Cahalan, Michael D
• Format: Journal Article
• Language: English
• Published: England eLife Sciences Publications Ltd 22-02-2022; eLife Sciences Publications, Ltd
• Subjects: Adenosine Diphosphate - metabolism; Alzheimer Disease - metabolism; Alzheimer's disease; Ca2+ signaling; Calcium (reticular); Calcium - metabolism; Calcium channels; Calcium influx; Calcium Signaling; Calcium signalling; Chemotaxis; Endoplasmic reticulum; Experiments; Homeostasis; Humans; Immunology and Inflammation; Induced Pluripotent Stem Cells - metabolism; iPSC-derived microglia; Membrane Glycoproteins - genetics; Membrane Glycoproteins - metabolism; Membrane proteins; Metabolites; Microglia; Microglia - metabolism; Motility; Myeloid cells; Neurodegenerative diseases; Neuroscience; P2Y receptor; Phagocytosis; Pluripotency; Receptors, Immunologic - metabolism; Receptors, Purinergic - metabolism; Stem cells; store-operated Ca2+ entry; TREM2; iPSC-derived microglia; Ca2+ signaling; inflammation; store-operated Ca2+ entry; P2Y receptor; neuroscience; TREM2; Alzheimer's disease; human; immunology
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/ELIFE.73021

The membrane protein TREM2 (Triggering Receptor Expressed on Myeloid cells 2) regulates key microglial functions including phagocytosis and chemotaxis. Loss-of-function variants of TREM2 are associated with increased risk of Alzheimer's disease (AD). Because abnormalities in Ca
signaling have been observed in several AD models, we investigated TREM2 regulation of Ca
signaling in human induced pluripotent stem cell-derived microglia (iPSC-microglia) with genetic deletion of TREM2. We found that iPSC-microglia lacking TREM2 (TREM2 KO) show exaggerated Ca
signals in response to purinergic agonists, such as ADP, that shape microglial injury responses. This ADP hypersensitivity, driven by increased expression of P2Y
and P2Y
receptors, results in greater release of Ca
from the endoplasmic reticulum stores, which triggers sustained Ca
influx through Orai channels and alters cell motility in TREM2 KO microglia. Using iPSC-microglia expressing the genetically encoded Ca
probe, Salsa6f, we found that cytosolic Ca
tunes motility to a greater extent in TREM2 KO microglia. Despite showing greater overall displacement, TREM2 KO microglia exhibit reduced directional chemotaxis along ADP gradients. Accordingly, the chemotactic defect in TREM2 KO microglia was rescued by reducing cytosolic Ca
using a P2Y
receptor antagonist. Our results show that loss of TREM2 confers a defect in microglial Ca
response to purinergic signals, suggesting a window of Ca
signaling for optimal microglial motility.