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The role of PI3Kγ in the immune system: new insights and translational implications

Abstract

Over the past two decades, new insights have positioned phosphoinositide 3-kinase-γ (PI3Kγ) as a context-dependent modulator of immunity and inflammation. Recent advances in protein structure determination and drug development have allowed for generation of highly specific PI3Kγ inhibitors, with the first now in clinical trials for several oncology indications. Recently, a monogenic immune disorder caused by PI3Kγ deficiency was discovered in humans and modelled in mice. Human inactivated PI3Kγ syndrome confirms the immunomodulatory roles of PI3Kγ and strengthens newly defined roles of this molecule in modulating inflammatory cytokine release in macrophages. Here, we review the functions of PI3Kγ in the immune system and discuss how our understanding of its potential as a therapeutic target has evolved.

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Fig. 1: Context-dependent signalling of PI3Kγ complexes.
Fig. 2: PI3Kγ complex regulation and mutations in human patients.
Fig. 3: Involvement of PI3Kγ and PI3Kβ in progression of atherosclerosis.
Fig. 4: Shared features of immunodeficiency and immunopathology from PI3Kγ deficiency in humans and mice.

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Acknowledgements

C.L.L. acknowledges funding from the National Institutes of Health (NIAID R21AI144315) and Mathers Foundation. The authors thank K. Jones for her helpful comments on their manuscript. M.P.W. was funded by the Swiss National Science Foundation (grants SNF 316030_198526 and 310030_189065), Innosuisse (grant 37213.1 IP-LS) and the Horizon 2020 project ITN 675392.

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Glossary

Primary immunodeficiency disorder

One of a collection of distinct rare disorders resulting from a gene defect that causes dysfunctional immune responses and recurrent infection.

Fatty streaks

Disintegrated foam cells (fat-loaded macrophages) that form a layer of fat beneath endothelial cells and disengage them from the extracellular matrix.

Thermogenesis

Production of (body) heat by short-circuiting mitochondria, for example, with uncoupling proteins.

Foam cells

Macrophages that has consumed degraded LDL particles and has a microscopic appearance of foam.

IPI-549

An oral and selective next-generation PI3Kγ inhibitor developed by Infinity Pharmaceuticals.

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Lanahan, S.M., Wymann, M.P. & Lucas, C.L. The role of PI3Kγ in the immune system: new insights and translational implications. Nat Rev Immunol 22, 687–700 (2022). https://doi.org/10.1038/s41577-022-00701-8

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