Signalling: PI3Kβ — linking signals for neutrophil activation
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Neutrophils mediate crucial innate immune responses to bacteria and fungi; however, their destruc- tive effector functions can also be responsible for the pathology associated with inflammatory dis- eases. Recent interest has focused on the roles of the γ-isoform of phosphoinositide 3-kinase (PI3Kγ) in neutrophil responses, but a new study now suggests that PI3Kβ may be a more relevant therapeutic target in disorders involving immune complex deposition, such as rheumatoid arthritis. PI3Ks are key components of numerous signalling pathways, with roles in cell survival, growth and motility. Furthermore, individual PI3K isoforms (particularly PI3Kγ and PI3Kδ) have been attributed non-redundant functions in immune responses. However, in many cases the contributions of particular isoforms have not been elucidated, so Kulkarni et al. set out to investigate the role of PI3Kβ in neutrophils. PI3Kβ-deficient neutrophils produced lower concentrations of reactive oxygen species (ROS) in response to immune complexes than control neutrophils. This impact of PI3Kβ deficiency was most pro- nounced at low immune complex densities, whereas at high densities PI3Kδ could partly substitute for the function of PI3Kβ in ROS genera- tion. Interestingly, however, PI3Kγ deficiency had no effect on this response. Conversely, PI3Kγ, but not PI3Kβ, was required for ROS production in response to other, G protein-coupled receptor (GPCR)- linked stimuli (including formyl peptides and leukotriene B4 (LTB4)), in accordance with previous studies. But what is the signalling mecha- nism responsible for these effects? Neutrophils detect IgG-containing immune complexes through Fc receptors for IgG (FcγRs), leading to tyrosine phosphorylation of the Fc receptor γ-chain (FcRγ). As expected, PI3Kβ was shown to act downstream of FcRγ phosphoryla- tion, but upstream of the protein kinase AKT. In addition, recent findings have indicated that the pro- inflammatory lipid LTB4 is involved in FcγR signalling in macrophages. This study explored this further in neutrophils, and suggests that LTB4 is produced in response to FcγR ligation and, following its release, signals in an autocrine or paracrine manner through its GPCR BLT1 (also known as LTB4R1) to enhance immune complex-induced ROS production. Intriguingly, this signal- ling loop in response to FcγR ligation was not abolished in PI3Kγ-deficient neutrophils, despite the known role for PI3Kγ downstream of BLT1. By blocking endogenous LTB4 produc- tion, the authors confirmed that the response to LTB4 alone required PI3Kγ, whereas the response to co- stimulation with LTB4 and immune complexes was largely dependent on PI3Kβ. Thus, the authors suggest that the unique ability of PI3Kβ to mediate signalling downstream of both tyrosine kinase-linked recep- tors and GPCRs may allow this isoform to integrate signals from FcγRs and BLT1, respectively, and could explain its crucial role in the response to immune complexes. So, do these findings have implications for treating inflamma- tory disorders? In a model of the autoantibody-induced blistering dis- ease epidermolysis bullosa acquisita, mice lacking PI3Kβ were markedly protected from disease development, even though the extent of immune complex deposition in the skin was equivalent to that of wild-type mice. By contrast, PI3Kβ-deficient mice were only partially protected in a mouse model of rheumatoid arthritis, but mice that were also deficient in the kinase activity of PI3Kδ were highly resistant to disease. Together with the finding that loss of PI3Kβ does not affect humoral responses or neutrophil-mediated killing of Staphylococcus aureus, these results suggest that inhibition of PI3Kβ might be an effective means to treat certain inflammatory conditions, without compromising protective immunity. Isabel Woodman ORIGINAL RESEARCH PAPER Kulkarni, S. et al. PI3Kβ plays a critical role in neutrophil activation by immune complexes. Sci. Signal. 4, ra23 (2011) SIGNALLING PI3Kβ — linking signals for neutrophil activation RESEARCH HIGHLIGHTS NATURE REVIEWS | IMMUNOLOGY VOLUME 11 | JUNE 2011 Nature Reviews Immunology | AOP, published online 20 May 2011; doi:10.1038/nri2994 © 2011 Macmillan Publishers Limited. All rights reserved
Transcript of Signalling: PI3Kβ — linking signals for neutrophil activation
Neutrophils mediate crucial innate immune responses to bacteria and fungi; however, their destruc-tive effector functions can also be responsible for the pathology associated with inflammatory dis-eases. Recent interest has focused on the roles of the γ-isoform of phosphoinositide 3-kinase (PI3Kγ) in neutrophil responses, but a new study now suggests that PI3Kβ may be a more relevant therapeutic target in disorders involving immune complex deposition, such as rheumatoid arthritis.
PI3Ks are key components of numerous signalling pathways, with roles in cell survival, growth and motility. Furthermore, individual PI3K isoforms (particularly PI3Kγ and PI3Kδ) have been attributed non-redundant functions in immune responses. However, in many cases the contributions of particular isoforms have not been elucidated, so Kulkarni et al. set out to investigate the role of PI3Kβ in neutrophils. PI3Kβ-deficient neutrophils produced lower concentrations of reactive oxygen species (ROS) in response to immune complexes than control neutrophils. This impact of PI3Kβ deficiency was most pro-nounced at low immune complex densities, whereas at high densities PI3Kδ could partly substitute for the function of PI3Kβ in ROS genera-tion. Interestingly, however, PI3Kγ deficiency had no effect on this
response. Conversely, PI3Kγ, but not PI3Kβ, was required for ROS production in response to other, G protein-coupled receptor (GPCR)-linked stimuli (including formyl peptides and leukotriene B4 (LTB4)), in accordance with previous studies.
But what is the signalling mecha-nism responsible for these effects? Neutrophils detect IgG-containing immune complexes through Fc receptors for IgG (FcγRs), leading to tyrosine phosphorylation of the Fc receptor γ-chain (FcRγ). As expected, PI3Kβ was shown to act downstream of FcRγ phosphoryla-tion, but upstream of the protein kinase AKT. In addition, recent findings have indicated that the pro-inflammatory lipid LTB4 is involved in FcγR signalling in macrophages. This study explored this further in neutrophils, and suggests that LTB4 is produced in response to FcγR ligation and, following its release, signals in an autocrine or paracrine manner through its GPCR BLT1 (also known as LTB4R1) to enhance immune complex-induced ROS production. Intriguingly, this signal-ling loop in response to FcγR ligation was not abolished in PI3Kγ-deficient neutrophils, despite the known role for PI3Kγ downstream of BLT1. By blocking endogenous LTB4 produc-tion, the authors confirmed that the response to LTB4 alone required PI3Kγ, whereas the response to co-stimulation with LTB4 and immune
complexes was largely dependent on PI3Kβ. Thus, the authors suggest that the unique ability of PI3Kβ to mediate signalling downstream of both tyrosine kinase-linked recep-tors and GPCRs may allow this isoform to integrate signals from FcγRs and BLT1, respectively, and could explain its crucial role in the response to immune complexes.
So, do these findings have implications for treating inflamma-tory disorders? In a model of the autoantibody-induced blistering dis-ease epidermolysis bullosa acquisita, mice lacking PI3Kβ were markedly protected from disease development, even though the extent of immune complex deposition in the skin was equivalent to that of wild-type mice. By contrast, PI3Kβ-deficient mice were only partially protected in a mouse model of rheumatoid arthritis, but mice that were also deficient in the kinase activity of PI3Kδ were highly resistant to disease. Together with the finding that loss of PI3Kβ does not affect humoral responses or neutrophil-mediated killing of Staphylococcus aureus, these results suggest that inhibition of PI3Kβ might be an effective means to treat certain inflammatory conditions, without compromising protective immunity.
Isabel Woodman
ORIGINAL RESEARCH PAPER Kulkarni, S. et al. PI3Kβ plays a critical role in neutrophil activation by immune complexes. Sci. Signal. 4, ra23 (2011)
S I G N A L L I N G
PI3Kβ — linking signals for neutrophil activation
R E S E A R C H H I G H L I G H T S
NATURE REVIEWS | IMMUNOLOGY VOLUME 11 | JUNE 2011
Nature Reviews Immunology | AOP, published online 20 May 2011; doi:10.1038/nri2994
© 2011 Macmillan Publishers Limited. All rights reserved
