PI3K signalling in inflammation

Area of Science:

• Immunology
• Cell Biology
• Biochemistry

Background:

• Phosphoinositide 3-kinases (PI3Ks) are critical regulators of cellular processes involved in inflammatory responses to infection and damage.
• Class I PI3K isoforms (α, β, γ, δ) synthesize phosphatidylinositol (3,4,5)-trisphosphate (PIP3), a second messenger regulating cell functions.
• PI3Kγ and PI3Kδ are highly expressed in leukocytes and play key roles in immune cell activation, development, and trafficking.

Purpose of the Study:

• To investigate the roles of different PI3K isoforms in inflammatory responses.
• To evaluate the therapeutic potential of isoform-selective PI3K inhibitors in models of chronic inflammation.

Main Methods:

• Utilized genetically-modified mice with altered PI3K signaling.
• Employed isoform-selective, small-molecule PI3K inhibitors.
• Assessed inflammation severity in various mouse models of autoimmune, respiratory, and allergic diseases.

Main Results:

• Selective inhibition of PI3Kδ, PI3Kγ, or PI3Kβ reduced inflammation severity in preclinical models.
• Dual inhibition of PI3Kγ/δ or PI3Kβ/δ demonstrated enhanced efficacy in reducing inflammation.
• Class II PI3Ks are involved in endocytosis, while Class III PI3K regulates autophagy and endosome-lysosome trafficking.

Conclusions:

• Targeting Class I PI3K isoforms, particularly PI3Kδ and PI3Kγ, offers a promising therapeutic strategy for treating non-resolving inflammatory diseases.
• Isoform-selective PI3K inhibition can modulate key pathways in innate and adaptive immunity, impacting inflammatory pathologies.