PI3K signalling in inflammation
Open accessAbstract
PI3Ks regulate several key events in the inflammatory response to damage and infection. There are four Class I PI3K isoforms (PI3Kα,β,γ,δ), three Class II PI3K isoforms (PI3KC2α, C2β, C2γ) and a single Class III PI3K. The four Class I isoforms synthesise the phospholipid 'PIP3'. PIP3 is a 'second messenger' used by many different cell surface receptors to control cell movement, growth, survival and differentiation. These four isoforms have overlapping functions but each is adapted to receive efficient stimulation by particular receptor sub-types. PI3Kγ is highly expressed in leukocytes and plays a particularly important role in chemokine-mediated recruitment and activation of innate immune cells at sites of inflammation. PI3Kδ is also highly expressed in leukocytes and plays a key role in antigen receptor and cytokine-mediated B and T cell development, differentiation and function. Class III PI3K synthesises the phospholipid PI3P, which regulates endosome-lysosome trafficking and the induction of autophagy, pathways involved in pathogen killing, antigen processing and immune cell survival. Much less is known about the function of Class II PI3Ks, but emerging evidence indicates they can synthesise PI3P and PI34P2 and are involved in the regulation of endocytosis. The creation of genetically-modified mice with altered PI3K signalling, together with the development of isoform-selective, small-molecule PI3K inhibitors, has allowed the evaluation of the individual roles of Class I PI3K isoforms in several mouse models of chronic inflammation. Selective inhibition of PI3Kδ, γ or β has each been shown to reduce the severity of inflammation in one or more models of autoimmune disease, respiratory disease or allergic inflammation, with dual γ/δ or β/δ inhibition generally proving more effective. The inhibition of Class I PI3Ks may therefore offer a therapeutic opportunity to treat non-resolving inflammatory pathologies in humans. This article is part of a Special Issue entitled Phosphoinositides.
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p110γ and p110δ both play important, non-redundant roles in the immune system.
“They both play important, non-redundant roles in the immune system [68–70].”
From Phosphatidylinositol(4,5)bisphosphate: diverse functions at the plasma membrane (2020) · cites this paper as [68]
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Cites
Origin and physiological roles of inflammation
Medzhitov, R. (2008) · Nature · doi:10.1038/nature07201 · Cited by 6,618 · see citing works
Neutrophil recruitment and function in health and inflammation
Kolaczkowska, E., & Kubes, P. (2013) · Nature Reviews Immunology · doi:10.1038/nri3399 · Cited by 5,472 · see citing works
Autophagy in immunity and inflammation
Levine, B., Mizushima, N., & Virgin, H. W. (2011) · Nature · doi:10.1038/nature09782 · Cited by 3,289 · see citing works
Towards a systems understanding of MHC class I and MHC class II antigen presentation
Neefjes, J., Jongsma, M. L. M., Paul, P., & Bakke, O. (2011) · Nature Reviews Immunology · doi:10.1038/nri3084 · Cited by 2,044 · see citing works
The functions and regulation of the PTEN tumour suppressor
Song, M. S., Salmena, L., & Pandolfi, P. P. (2012) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3330 · Cited by 1,926 · see citing works
Victora, G. D., & Nussenzweig, M. C. (2012) · Annual Review of Immunology · doi:10.1146/annurev-immunol-020711-075032 · Cited by 1,878 · see citing works
The SYK tyrosine kinase: A crucial player in diverse biological functions
Mócsai, A., Ruland, J., & Tybulewicz, V. L. J. (2010) · Nature Reviews Immunology · doi:10.1038/nri2765 · Cited by 1,368 · see citing works
Shaping cups into phagosomes and macropinosomes
Swanson, J. A. (2008) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2447 · Cited by 941 · see citing works
Signalling through Class I PI3Ks in mammalian cells
Hawkins, P. T., Anderson, K. E., Davidson, K., & Stephens, L. R. (2006) · Biochemical Society Transactions · doi:10.1042/bst0340647 · Cited by 540 · see citing works
Self-citationA highly potent and selective Vps34 inhibitor alters vesicle trafficking and autophagy
Ronan, B., Flamand, O., Vescovi, L., Dureuil, C., Durand, L., Fassy, F., Bachelot, M.-F., Lamberton, A., Mathieu, M., Bertrand, T., et al. (2014) · Nature Chemical Biology · doi:10.1038/nchembio.1681 · Cited by 500 · see citing works
Structural Basis for Activation and Inhibition of Class I Phosphoinositide 3-Kinases
Vadas, O., Burke, J. E., Zhang, X., Berndt, A., & Williams, R. L. (2011) · Science Signaling · doi:10.1126/scisignal.2002165 · Cited by 299 · see citing works
Allan, E. R. O., Tailor, P., Balce, D. R., Pirzadeh, P., McKenna, N. T., Renaux, B., Warren, A. L., Jirik, F. R., & Yates, R. M. (2014) · The Journal of Immunology · doi:10.4049/jimmunol.1302896 · Cited by 95 · see citing works
Flagged first, then by citations
Research works printed but not linked: 9
- D.K. Finlay, mTORC1 regulates CD8+ T-cell glucose metabolism and function independently of PI3K and PKB, Biochem. Soc. Trans. 41 (2013) 681-686.
- B. Kurig, A. Shymanets, T. Bohnacker, Brock C. Prajwal, et al., Ras is an indispensable coregulator of the class IB phosphoinositide 3-kinase p87/p110gamma, Proc. Natl. Acad. Sci. U. S. A. 106 (2009) 20312-20317.
- O. Vadas, H.A. Dbouk, A. Shymanets, O. Perisic, J.E. Burke, et al., Molecular determinants of PI3Kgamma-mediated activation downstream of G-protein-coupled receptors (GPCRs), Proc. Natl. Acad. Sci. U. S. A. 110 (2013) 18862-18867.
- J.D. Chang, G.K. Sukhova, P. Libby, E. Schvartz, A.H. Lichtenstein, et al., Deletion of the phosphoinositide 3-kinase p110gamma gene attenuates murine atherosclerosis, Proc. Natl. Acad. Sci. U. S. A. 104 (2007) 8077-8082.
- J. Guillermet-Guibert, K. Bjorklof, A. Salpekar, C. Gonella, F. Ramadani, et al., The p110beta isoform of phosphoinositide 3-kinase signals downstream of G protein-coupled receptors and is functionally redundant with p110gamma, Proc. Natl. Acad. Sci. U. S. A. 105 (2008) 8292-8297.
- M.J. Rauh, J. Kalesnikoff, M. Hughes, L. Sly, V. Lam, et al., Role of Src homology 2-containing-inositol 5'-phosphatase (SHIP) in mast cells and macrophages, Biochem. Soc. Trans. 31 (2003) 286-291.
- M. Gigoux, J. Shang, Y. Pak, M. Xu, J. Choe, et al., Inducible costimulator promotes helper T-cell differentiation through phosphoinositide 3-kinase, Proc. Natl. Acad. Sci. U. S. A. 106 (2009) 20371-20376.
- W.C. Rowan, J.L. Smith, K. Affleck, A. Amour, Targeting phosphoinositide 3-kinase delta for allergic asthma, Biochem. Soc. Trans. 40 (2012) 240-245.
- T. Willinger, R.A. Flavell, Canonical autophagy dependent on the class III phosphoinositide-3 kinase Vps34 is required for naive T-cell homeostasis, Proc. Natl. Acad. Sci. U. S. A. 109 (2012) 8670-8675.
Cited by
Sorted by citations
The PI3K Pathway in Human Disease
Fruman, D. A., Chiu, H., Hopkins, B. D., Bagrodia, S., Cantley, L. C., & Abraham, R. T. (2017) · Cell · doi:10.1016/j.cell.2017.07.029 · Cited by 2,749 · see citing works
Modulation of inflammation by autophagy: Consequences for human disease
Netea-Maier, R. T., Plantinga, T. S., van de Veerdonk, F. L., Smit, J. W., & Netea, M. G. (2016) · Autophagy · doi:10.1080/15548627.2015.1071759 · Cited by 349 · see citing works
Structural Basis for Regulation of Phosphoinositide Kinases and Their Involvement in Human Disease
Burke, J. E. (2018) · Molecular Cell · doi:10.1016/j.molcel.2018.08.005 · Cited by 276 · see citing works
PTEN Regulates PI(3,4)P2 Signaling Downstream of Class I PI3K
Malek, M., Kielkowska, A., Chessa, T., Anderson, K. E., Barneda, D., Pir, P., Nakanishi, H., Eguchi, S., Koizumi, A., Sasaki, J., et al. (2017) · Molecular Cell · doi:10.1016/j.molcel.2017.09.024 · Cited by 190 · see citing works
Self-citationPhosphatidylinositol(4,5)bisphosphate: diverse functions at the plasma membrane
Katan, M., & Cockcroft, S. (2020) · Essays in Biochemistry · doi:10.1042/ebc20200041 · Cited by 176 · see citing works
Dysregulated phosphoinositide 3-kinase signaling in microglia: shaping chronic neuroinflammation
Chu, E., Mychasiuk, R., Hibbs, M. L., & Semple, B. D. (2021) · Journal of Neuroinflammation · doi:10.1186/s12974-021-02325-6 · Cited by 152 · see citing works
The Pathogenesis and Immune Evasive Mechanisms of Equine Herpesvirus Type 1
Laval, K., Poelaert, K. C. K., Van Cleemput, J., Zhao, J., Vandekerckhove, A. P., Gryspeerdt, A. C., Garré, B., van der Meulen, K., Baghi, H. B., Dubale, H. N., et al. (2021) · Frontiers in Microbiology · doi:10.3389/fmicb.2021.662686 · Cited by 54 · see citing works
“PI3K isoform γ is highly expressed in leukocytes and triggers chemokine-mediated recruitment and activation of innate immune cells at inflammation sites (Hawkins and Stephens, 2015).”
BackgroundNew targets to alleviate skeletal muscle inflammation: Role of microRNAs regulated by adiponectin
Boursereau, R., Abou-Samra, M., Lecompte, S., Noel, L., & Brichard, S. M. (2017) · Scientific Reports · doi:10.1038/srep43437 · Cited by 18 · see citing works
- Authors
- Hawkins, P. T., & Stephens, L. R.
- Affiliations
- Babraham Institute (GB)
- Corresponding author
- Hawkins, P.T.
- Stephens, L.R.
- Venue
- Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids
- Publisher
- Elsevier BV
- Published
- 2015-06
- Volume
- 1851
- Issue
- 6
- Pages
- 882-897
- ISSN
- 1388-1981 (ISSN-L)
- OpenAlex
- W2028549997
- Cited by
- 541
- References
- 12
- Citations by year
- 2026: 33 · 2025: 55 · 2024: 45 · 2023: 56 · 2022: 52 · 2021: 66 · 2020: 45 · 2019: 60 · 2018: 44 · 2017: 43 · 2016: 24 · 2015: 15 · 2014: 1 · 2012: 1
- FWCI
- 2.60
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Biotechnology and Biological Sciences Research Council (ISPG BB/J004456/1)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- PI3K signaling, inflammation, class II PI3K, class III PI3K, phosphatidylinositol 3,4,5-trisphosphate, phosphatidylinositol 3-phosphate, PI3Kδ, PI3Kγ, PI3Kβ, PI3K inhibitors, leukocyte chemotaxis, autophagy, endocytosis, autoimmune disease, allergic inflammation, respiratory diseases, chronic inflammation
- MeSH terms
- Phosphoinositide-3 Kinase Inhibitors, Animals, Autophagy, Biological Transport, Enzyme Inhibitors, Gene Expression Regulation, Humans, Immunity, Innate, Inflammation, Isoenzymes, Mice, Transgenic, Phosphatidylinositols, Endosomes, Signal Transduction, Phosphatidylinositol 3-Kinases, Mice
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