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PI3Kδ and PI3Kγ: partners in crime in inflammation in rheumatoid arthritis and beyond?

Key Points

  • Phosphoinositide 3-kinases (PI3Ks) generate lipid-based second messengers that control an array of intracellular signalling pathways that are responsible for many cellular functions, such as growth and proliferation, survival and apoptosis, as well as adhesion and migration.

  • Two isoforms of the class I PI3K family, PI3Kδ and PI3Kγ, are mainly expressed by cells of the haematopoietic system, in which they have a crucial role in signalling downstream of numerous receptors, such as cytokine receptors, G-protein-coupled receptors, receptor tyrosine kinases, Toll-like receptors and antigen receptors.

  • Experimental models of immune-based and inflammatory diseases using either gene-modified mice or pharmacological inhibitors of PI3Kδ and PI3Kγ have helped to identify the crucial functions of these PI3K isoforms, indicating that they have important non-redundant roles in mast cells, neutrophils, dendritic cells, B cells and T cells.

  • In some cellular responses, such as the generation of reactive oxygen species by neutrophils and the degranulation by mast cells, both PI3Kδ and PI3Kγ seem to be required. This favours a model in which the contribution of PI3Kδ and PI3Kγ is coordinated at different stages of signalling in these cells.

  • The potential of PI3Kδ and PI3Kγ as drug targets for the intervention of inflammatory and allergic disorders is also addressed.

  • Recent studies are highlighted showing that targeting PI3K isoforms can reduce glomerulonephritis in a mouse model of systemic lupus erythematosus and suppresses the progression of disease in mouse models of rheumatoid arthritis.

Abstract

Dysregulated signal transduction in innate and adaptive immune cells is known to be associated with the development of various autoimmune and inflammatory diseases. Consequently, targeting intracellular signalling of the pro-inflammatory cytokine network heralds hope for the next generation of anti-inflammatory drugs. Phosphoinositide 3-kinases (PI3Ks) generate lipid-based second messengers that control an array of intracellular signalling pathways that are known to have important roles in leukocytes. In light of the recent progress in the development of selective PI3K inhibitors, and the beneficial effects of these inhibitors in models of acute and chronic inflammatory disorders, we discuss the therapeutic potential of blocking PI3K isoforms for the treatment of rheumatoid arthritis and other immune-mediated diseases.

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Figure 1: Class I PI3Ks: linking cell-surface receptors to signalling networks and cell functions.
Figure 2: PI3K acts at multiple steps and various stages in the pathogenesis of rheumatoid arthritis.
Figure 3: Model for cooperativity between PI3Kδ and PI3Kγ in respiratory burst in neutrophils.
Figure 4: Model for cooperativity between PI3Kδ and PI3Kγ in degranulation in mast cells.

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Acknowledgements

We thank all our friends and colleagues, in particular, B. Vanhaesebroeck, M. Wymann, A. Carrera, E. Hirsch, R. Williams, P. Hawkins, L. Stephens, D. Lee and F. Rintelen for many insightful discussions. We further thank B. Vanhaesebroeck and R. Hooft for their kind and valuable support during the preparation of this Review. We also acknowledge the constructive and helpful suggestions provided by the anonymous referees. We are grateful to C. Hebert for all the original graphic work and to all our friends and colleagues for their outstanding support and contributions to our research.

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Correspondence to Christian Rommel.

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Christian Rommel, Montserrat Camps and Hong Ji are employed by Merck Serono International S.A., which is involved in the discovery and the commercialization of therapeutics for the prevention and treatment of human diseases.

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FURTHER INFORMATION

PI3K signalling in immune cells

Glossary

G-protein-coupled receptors

(GPCRs). One of a large group of seven-transmembrane-spanning receptors that bind a diverse set of molecules, including chemokines, complement components, bioactive amines, hormones and neurotransmitters. GPCRs are coupled to heterotrimeric, GTP-binding proteins composed of α and βγ subunits, which, after receptor activation by ligand binding, split into α monomers and βγ dimers, which interact and activate or inhibit downstream components of various signalling pathways.

Mammalian target of rapamycin

(MTOR). MTOR is a conserved serine/threonine protein kinase that regulates cell growth and metabolism, as well as cytokine and growth-factor expression, in response to environmental cues. MTOR receives stimulatory signals from RAS and phosphoinositide 3-kinase (PI3K) downstream of growth factors, as well as nutrients, such as amino acids, glucose and oxygen.

Anaphylaxis

Severe and rapid allergic reaction triggered by the activation of high-affinity Fc receptors for IgE in sensitized individuals. An anaphylactic shock is the most severe type of anaphylaxis and will usually lead to death in minutes if left untreated.

MRL–lpr mouse

A mouse strain that spontaneously develops glomerulonephritis and other symptoms of systemic lupus erythematosus (SLE). The lpr mutation causes a defect in FAS (also known as CD95), preventing the apoptosis of activated lymphocytes; the MRL strain contributes disease-associated mutations that have yet to be identified.

Pannus

A sheet of inflammatory granulation tissue, composed of immune cells, blood vessels and fibrous cells, that spreads from the synovial membrane and ultimately invades the joint in rheumatoid arthritis.

Collagen-induced arthritis

An animal model of rheumatoid arthritis. Collagen-induced arthritis develops in susceptible rodents and primates after immunization with cartilage-derived type II collagen.

Contact hypersensitivity

A T-cell-mediated immune response that is evoked following antigen administration in the skin. It is marked by monocyte and/or macrophage infiltration and activation, and depends on the production of T-helper-1-type cytokines.

Respiratory burst

A large increase in oxygen consumption and reactive oxygen species generation that accompanies the exposure of neutrophils to microorganisms and/or inflammatory mediators.

Pertussis toxin

Pertussis toxin blocks Gαi-coupled receptor signalling (including chemokine-receptor signalling) by catalysing ADP ribosylation of the Gαi subunit.

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Rommel, C., Camps, M. & Ji, H. PI3Kδ and PI3Kγ: partners in crime in inflammation in rheumatoid arthritis and beyond?. Nat Rev Immunol 7, 191–201 (2007). https://doi.org/10.1038/nri2036

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