Related Experiment Video
Updated: Jun 28, 2025
In vitro Quantitative Imaging Assay for Phagocytosis of Dead Neuroblastoma Cells by iPSC-Macrophages
Published on: February 14, 2021
SHIP inhibition mediates select TREM2-induced microglial functions
Gautham S Ramakrishnan1, William L Berry2, Angela Pacherille3
1Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
Abstract:
Microglia play a pivotal role in the pathology of Alzheimer's Disease (AD), with the Triggering Receptor Expressed on Myeloid cells 2 (TREM2) central to their neuroprotective functions. The R47H variant of TREM2 has emerged as a significant genetic risk factor for AD, leading to a loss-of-function phenotype in mouse AD models. This study elucidates the roles of TREM2 in human microglia-like HMC3 cells and the regulation of these functions by SH2-containing inositol-5'-phosphatase 1 (SHIP1). Using stable cell lines expressing wild-type TREM2, the R47H variant, and TREM2-deficient lines, we found that functional TREM2 is essential for the phagocytosis of Aβ, lysosomal capacity, and mitochondrial activity. Notably, the R47H variant displayed increased phagocytic activity towards apoptotic neurons. Introducing SHIP1, known to modulate TREM2 signaling in other cells, revealed its role as a negative regulator of these TREM2-mediated functions. Moreover, pharmacological inhibition of both SHIP1 and its isoform SHIP2 amplified Aβ phagocytosis and lysosomal capacity, independently of TREM2 or SHIP1 expression, suggesting a potential regulatory role for SHIP2 in these functions. The absence of TREM2, combined with the presence of both SHIP isoforms, suppressed mitochondrial activity. However, pan-SHIP1/2 inhibition enhanced mitochondrial function in these cells. In summary, our findings offer a deeper understanding of the relationship between TREM2 variants and SHIP1 in microglial functions, and emphasize the therapeutic potential of targeting the TREM2 and SHIP1 pathways in microglia for neurodegenerative diseases.
Insights
Triggering Receptor Expressed on Myeloid cells 2 (TREM2) is crucial for microglial neuroprotection in Alzheimer's Disease (AD). This study shows SH2-containing inositol-5'-phosphatase 1 (SHIP1) negatively regulates TREM2 functions, offering therapeutic insights.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Microglia are key players in Alzheimer's Disease (AD) pathology.
- Triggering Receptor Expressed on Myeloid cells 2 (TREM2) is vital for microglial neuroprotective functions.
- The TREM2 R47H variant is a significant genetic risk factor for AD, associated with loss-of-function.
Purpose of the Study:
- To investigate the role of TREM2 in human microglia-like HMC3 cells.
- To explore the regulatory function of SH2-containing inositol-5 omino-phosphatase 1 (SHIP1) on TREM2-mediated microglial functions.
- To assess the impact of TREM2 variants and SHIP1 modulation on microglial phagocytosis, lysosomal capacity, and mitochondrial activity.
Main Methods:
- Utilized stable human microglia-like HMC3 cell lines expressing wild-type TREM2, R47H variant, or deficient in TREM2.
- Assessed phagocytosis of amyloid-beta (Aβ) and apoptotic neurons.
- Measured lysosomal capacity and mitochondrial activity.
- Investigated the effects of SHIP1 introduction and pharmacological inhibition of SHIP1/SHIP2.
Main Results:
- Functional TREM2 is essential for Aβ phagocytosis, lysosomal capacity, and mitochondrial activity.
- The TREM2 R47H variant showed enhanced phagocytosis of apoptotic neurons.
- SHIP1 acts as a negative regulator of TREM2-mediated functions.
- Inhibition of SHIP1 and SHIP2 enhanced Aβ phagocytosis and lysosomal capacity.
- SHIP1/2 inhibition improved mitochondrial function in TREM2-deficient cells.
Conclusions:
- TREM2 plays a critical role in essential microglial functions relevant to AD.
- SHIP1 negatively regulates TREM2-dependent microglial activities.
- Targeting TREM2 and SHIP1 pathways presents a potential therapeutic strategy for neurodegenerative diseases like AD.
