Regulation of FcγR-stimulated phagocytosis by the 72-kDa inositol polyphosphate 5-phosphatase: SHIP1, but not the 72-kDa 5-phosphatase, regulates complement receptor 3–mediated phagocytosis by differential recruitment of these 5-phosphatases to the phagocytic cup
Abstract
Macrophages phagocytose particles to resolve infections and remove apoptotic cells. Phosphoinositide 3-kinase generates phosphatidylinositol-3,4,5-trisphosphate [PtdIns(3,4,5)P(3)] is restricted to the phagocytic cup, promoting phagocytosis. The PtdIns(3,4,5)P(3) 5-phosphatase (5-ptase) Src homology 2 (SH2) domain-containing inositol-5-phosphatase 1 (SHIP1) inhibits phagocytosis. We report here that another PtdIns(3,4,5)P(3)-5-ptase, the 72-kDa-5-phosphatase (72-5ptase), inhibits Fcgamma receptor (FcgammaR)- but not complement receptor 3 (CR3)-mediated phagocytosis, affecting pseudopod extension and phagosome closure. In contrast, SHIP1 inhibited FcgammaR and CR3 phagocytosis with greater effects on CR3-stimulated phagocytosis. The 72-5ptase and SHIP1 were both dynamically recruited to FcgammaR-stimulated phagocytic cups, but only SHIP1 was recruited to CR3-stimulated phagocytic cups. To determine whether 5-ptases focally degrade PtdIns(3,4,5)P(3) at the phagocytic cup after specific stimuli, time-lapse imaging of specific biosensors was performed. Transfection of dominant-negative 72-5ptase or 72-5ptase small interfering RNA (siRNA) resulted in amplified and prolonged PtdIns(3,4,5)P(3) at the phagocytic cup in response to FcgammaR- but not CR3-stimulation. In contrast, macrophages from Ship1(-/-)/AktPH-GFP transgenic mice exhibited increased and sustained PtdIns(3,4,5)P(3) at the cup in response to CR3 activation, with minimal changes to FcgammaR activation. Therefore, 72-5p…
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Constitutive deletion or pharmacologic inhibition of SHIP1 increases phagocytosis of various substances, including zymosan in SHIP1 knockout macrophages and Aβ in SHIP1 inhibitor-treated microglia.
“Constitutive deletion or pharmacologic inhibition of SHIP1 increases phagocytosis of various substances, including zymosan in SHIP1 knockout (KO) macrophages and Aβ in SHIP1 inhibitor-treated microglia.12,13”
From Microglial <i>INPP5D</i> limits plaque formation and glial reactivity in the PSAPP mouse model of Alzheimer's disease (2023) · cites this paper as [13]
Microglia with decreased Inpp5d or in the presence of a SHIP1 inhibitor demonstrated increased phagocytosis.
“Moreover, microglia with decreased Inpp5d or in the presence of a SHIP1 inhibitor, demonstrated increased phagocytosis.12,13”
From Microglial <i>INPP5D</i> limits plaque formation and glial reactivity in the PSAPP mouse model of Alzheimer's disease (2023) · cites this paper as [13]
SHIP1 deficiency has been associated with increased phagocytosis of various substrates in other models.
“However, SHIP1 deficiency has been associated with increased phagocytosis of various substrates in other models73,74.”
From INPP5D/SHIP1 regulates endo-lysosomal function and cargo-selective phagocytosis in human microglia (2025) · cites this paper as [73]
In mouse macrophages and COS cells, SHIP1 activates the ITIM of the inhibitory receptor FCγRIIβ, which inhibits the activating receptor FCγRIIA to block FCγRIIA-mediated phagocytosis.
“In mouse macrophages and COS cells, SHIP1 was shown to activate the ITIM of the inhibitory receptor FCγRIIβ, which inhibits the activating receptor FCγRIIA to block FCγRIIA-mediated phagocytosis (Fig. 3C).”
From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [134]
SHIP1 directly inhibits FCγRIIA by binding to its ITAM, which prevents activation of PI3K.
“SHIP1 also was shown to directly inhibit FCγRIIA by binding to its ITAM (Fig. 3C), which prevents the activation of PI3K [134, 137–140].”
From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [134]
SHIP1 modulates CR3-mediated phagocytosis in macrophages.
“SHIP1 also has been shown to modulate complement receptor 3 (CR3)-mediated phagocytosis in macrophages [134, 138, 141].”
From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [134]
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Tao, H., Yancey, P. G., Babaev, V. R., Blakemore, J. L., Zhang, Y., Ding, L., Fazio, S., & Linton, M. F. (2015) · Journal of Lipid Research · doi:10.1194/jlr.m056689 · Cited by 143 · see citing works
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<i>INPP5D</i> deficiency attenuates amyloid pathology in a mouse model of Alzheimer's disease
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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
- Horan, K. A., Watanabe, K.-I., Kong, A. M., Bailey, C. G., Rasko, J. E. J., Sasaki, T., & Mitchell, C. A.
- Affiliations
- Monash University (AU)
- Department of Pathology and Immunology, Akita University School of Medicine, Hondo, Japan;
- The University of Sydney (AU)
- Akita University (JP)
- ORCID
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2007-12-15
- Volume
- 110
- Issue
- 13
- Pages
- 4480-4491
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- OpenAlex
- W2061923742
- Cited by
- 45
- References
- 3
- Citations by year
- 2026: 3 · 2025: 1 · 2024: 1 · 2023: 2 · 2022: 3 · 2021: 1 · 2020: 2 · 2019: 2 · 2018: 1 · 2017: 2 · 2016: 5 · 2015: 3 · 2014: 4 · 2013: 3 · 2012: 5
- FWCI
- 0.74
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Blood (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- Fc gamma receptor, complement receptor 3, phagocytosis, SHIP1, phosphatidylinositol 3,4,5-trisphosphate, phosphatidylinositol 3-kinase, phagocytic cup, pseudopod extension, macrophages, efferocytosis, innate immunity regulation
- MeSH terms
- Inositol Polyphosphate 5-Phosphatases, Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases, Phosphoinositide 5-Phosphatases, Animals, Cell Line, Macrophages, Mice, Transgenic, Phagocytosis, Phosphoric Monoester Hydrolases, Pseudopodia, Macrophage-1 Antigen, Receptors, IgG, Protein Transport, Mice
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