Abstract
Human genetic studies have linked rare coding variants in microglial genes, such as TREM2, and more recently PLCG2 to Alzheimer's disease (AD) pathology. The P522R variant in PLCG2 has been shown to confer protection for AD and to result in a subtle increase in enzymatic activity. PLC gamma 2 is a key component of intracellular signal transduction networks and induces Ca2+ signals downstream of many myeloid cell surface receptors, including TREM2. To explore the relationship between PLC gamma 2 and TREM2 and the role of PLC gamma 2 in regulating immune cell function, we generated human induced pluripotent stem cell (iPSC)- derived macrophages from isogenic lines with homozygous PLCG2 knockout (Ko). Stimulating TREM2 signalling using a polyclonal antibody revealed a complete lack of calcium flux and IP1 accumulation in PLC gamma 2 Ko cells, demonstrating a non-redundant role of PLC gamma 2 in calcium release downstream of TREM2. Loss of PLC gamma 2 led to broad changes in expression of several macrophage surface markers and phenotype, including reduced phagocytic activity and survival, while LPS-induced secretion of the inflammatory cytokines TNF alpha and IL-6 was unaffected. We identified additional deficits in PLC gamma 2- deficient cells that compromised cellular adhesion and migration. Thus, PLC gamma 2 is key in enabling divergent cellular functions and might be a promising target to increase beneficial microglial functions.
| Dokumententyp: | Zeitschriftenartikel |
|---|---|
| Fakultät: | Medizin |
| Themengebiete: | 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit |
| ISSN: | 2045-2322 |
| Sprache: | Englisch |
| Dokumenten ID: | 100905 |
| Datum der Veröffentlichung auf Open Access LMU: | 05. Jun. 2023, 15:36 |
| Letzte Änderungen: | 17. Okt. 2023, 15:06 |
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