SHIP1 and its role for innate immune regulation—Novel targets for immunotherapy
Open accessAbstract
Phosphoinositide-3-kinase/AKT (PI3K/AKT) signaling plays key roles in the regulation of cellular activity in both health and disease. In immune cells, this PI3K/AKT pathway is critically regulated by the phosphoinositide phosphatase SHIP1, which has been reported to modulate the function of most immune subsets. In this review, we summarize our current knowledge of SHIP1 with a focus on innate immune cells, where we reflect on the most pertinent aspects described in the current literature. We also present several small-molecule agonists and antagonists of SHIP1 developed over the last two decades, which have led to improved outcomes in several preclinical models of disease. We outline these promising findings and put them in relation to human diseases with unmet medical needs, where we discuss the most attractive targets for immune therapies based on SHIP1 modulation.
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Dysfunction of SHIP1 has been associated with a spectrum of diseases, including AD, AML, SLE, RA.
“As such, dysfunction of SHIP1 has been associated with a spectrum of diseases, including Alzheimer’s disease (AD), acute myeloid leukemia (AML) and autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA)3–6.”
From INPP5D/SHIP1 regulates endo-lysosomal function and cargo-selective phagocytosis in human microglia (2025) · cites this paper as [5]
SHIP1 is primarily expressed in myeloid cells.
“SHIP1 is primarily expressed in myeloid cells”
From INPP5D/SHIP1 regulates endo-lysosomal function and cargo-selective phagocytosis in human microglia (2025) · cites this paper as [5]
SHIP1 deficiency has been implicated in various diseases of the immune system, such as acute myeloid leukemia (AML) and systemic lupus erythematosus (SLE).
“SHIP1 deficiency has been implicated in various diseases of the immune system, such as acute myeloid leukemia (AML) and systemic lupus erythematosus (SLE)3–5.”
From INPP5D/SHIP1 regulates endo-lysosomal function and cargo-selective phagocytosis in human microglia (2025) · cites this paper as [5]
SHIP1 can suppress inflammation by supporting anti-inflammatory cytokine activity.
“While SHIP1 downregulates pro-inflammatory cytokine production, it also can suppress inflammation by supporting anti-inflammatory cytokine activity [131].”
From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [131]
In macrophages, IL-10 suppresses TNF-α secretion, which is promoted by both phosphatase-dependent and -independent activities of SHIP1.
“In macrophages, the anti-inflammatory cytokine IL-10 can suppress TNF-α secretion, which is promoted by both phosphatase-dependent and -independent activities of SHIP1 [131–133].”
From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [131]
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References 219 · Cited by 14
- Authors
- Yeoh, W. J., & Krebs, P.
- Affiliations
- University of Bern (CH)
- Corresponding author
- Yeoh, Wen Jie
- Krebs, Philippe
- Venue
- European Journal of Immunology
- Publisher
- Wiley
- Published
- 2023-10-27
- Volume
- 53
- Issue
- 12
- Pages
- e2350446-e2350446
- ISSN
- 0014-2980 (ISSN-L)
- 1521-4141
- OpenAlex
- W4386993778
- Cited by
- 14
- References
- 219
- Citations by year
- 2026: 6 · 2025: 3 · 2024: 4 · 2023: 1
- FWCI
- 0.37
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- European Journal of Immunology (publishedVersion, other-oa)
- PubMed (publishedVersion)
- Bern Open Repository and Information System (University of Bern) (submittedVersion, cc-by)
- Open Access CRIS of the University of Bern
- Funders
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (310030_189185)
- Lungenliga Schweiz
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Keywords
- SHIP1, phosphoinositide phosphatase, PI3K/Akt signaling, innate immunity, innate immune cells, immunotherapy targets, immune regulation
- MeSH terms
- Inositol Polyphosphate 5-Phosphatases, Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases, Humans, Immunity, Innate, Immunotherapy, Phosphoric Monoester Hydrolases, Signal Transduction, Phosphatidylinositol 3-Kinases, Proto-Oncogene Proteins c-akt
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