SHIP inhibition mediates select TREM2-induced microglial functions
Open accessAbstract
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 func…
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SHIP1's inhibition of TREM2 signaling has been suggested as one of the mechanisms by which SHIP1 regulates phagocytosis.
“SHIP1’s inhibition of TREM2 signaling has been suggested as one of the mechanisms by which SHIP1 regulates phagocytosis54,55.”
From INPP5D/SHIP1 regulates endo-lysosomal function and cargo-selective phagocytosis in human microglia (2025) · cites this paper as [55]
One mechanism by which SHIP1 deficiency increases the phagocytosis of lipid-rich substrates is through upregulation of TREM2 signaling.
“We confirmed that one mechanism by which SHIP1 deficiency increases the phagocytosis of lipid-rich substrates is through upregulation of TREM2 signaling (Figures 6D-G, S6E) in line with previous reports55,57.”
From INPP5D/SHIP1 regulates endo-lysosomal function and cargo-selective phagocytosis in human microglia (2025) · cites this paper as [55]
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TREM2 Maintains Microglial Metabolic Fitness in Alzheimer’s Disease
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The Trem2 R47H variant confers loss-of-function-like phenotypes in Alzheimer's disease
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TREM2 promotes Aβ phagocytosis by upregulating C/EBPα-dependent CD36 expression in microglia
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Pan-SHIP1/2 inhibitors promote microglia effector functions essential for CNS homeostasis
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Microglial phagocytosis in Alzheimer disease
Brown, G. C., St George-Hyslop, P., Paolicelli, R. C., & Lemke, G. (2026) · Nature Reviews Neurology · doi:10.1038/s41582-025-01162-y · Cited by 36 · see citing works
INPP5D/SHIP1 regulates endo-lysosomal function and cargo-selective phagocytosis in human microglia
Terzioglu, G., Karp, E. S., Heuer, S. E., Chadarevian, J. P., Ahsan, F. M., Haage, V. C., Davtyan, H., Fogo, G. M., Curle, A. J., Ashour, N., et al. (2025) · doi:10.1101/2025.10.27.684632 · Cited by 3 · see citing works
- Authors
- Ramakrishnan, G. S., Berry, W. L., Pacherille, A., Kerr, W. G., Chisholm, J. D., Pedicone, C., & Humphrey, M. B.
- Affiliations
- University of Oklahoma Health Sciences Center (US)
- OU Health Stephenson Cancer Center (US)
- Syracuse University (US)
- SUNY Upstate Medical University (US)
- Icahn School of Medicine at Mount Sinai (US)
- Oklahoma City VA Medical Center (US)
- Corresponding author
- Humphrey, Mary Beth
- Venue
- Molecular Immunology
- Publisher
- Elsevier BV
- Published
- 2024-06
- Volume
- 170
- Pages
- 35-45
- ISSN
- 0161-5890 (ISSN-L)
- PMC
- PMC11097602
- OpenAlex
- W4394779446
- Cited by
- 17
- References
- 9
- Citations by year
- 2026: 8 · 2025: 9
- FWCI
- 2.63
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Molecular Immunology (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (RO1 AG059717)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Keywords
- TREM2, SHIP1, SHIP2, microglia, Alzheimer's disease, amyloid-beta phagocytosis, lysosomal function, mitochondrial activity, HMC3 cells, neuroinflammation, neuroprotection
- MeSH terms
- Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases, Alzheimer Disease, Animals, Cell Line, Humans, Lysosomes, Membrane Glycoproteins, Mitochondria, Phagocytosis, Receptors, Immunologic, Signal Transduction, Amyloid beta-Peptides, Apoptosis, Microglia
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