Abstract
Phosphoinositide-3 kinases (PI3Ks) generate 3-phosphorylated phosphoinositide lipids that are implicated in many biological processes in homeostatic states and pathologies such as cancer, inflammation and autoimmunity. Eight isoforms of PI3K exist in mammals and among them the class I PI3K, p110γ, and PI3Kδ, and class III Vps34 being the most expressed and well characterized in immune cells. Following engagement of pathogen recognition receptors (PRRs), PI3Ks coordinate vital cellular processes of signaling and vesicular trafficking in innate phagocytes such as macrophages and professional antigen presenting dendritic cells (DCs). Although previous studies demonstrated the involvement of PI3K isoforms in innate and adaptive immune cell types, the role of PI3Ks with respect to DC biology has been enigmatic. Thus, this review, based on studies involving PI3K isoforms, highlight how the different PI3Ks isoforms could regulate DC functions such as antigen processing and presentation including PRR responses.
Highlights
Phosphoinositide-3 kinases (PI3Ks) are activated by diverse signaling pathways including small G proteins of Ras and Rac family, tyrosine kinases- or G-protein- coupled receptors [1]
This study has shown that PI3Kδ mediates the switch between TIRAP-dependent pro-inflammatory pathway coupled to TLR4 endocytosis and TIRAP degradation subsequently leading to TRAM-dependent type I IFNβ and IL-10 secretion [8]
PI3Kγ was shown to play a key role in dendritic cells (DC) trafficking and in the activation of specific immunity since PI3Kγ deficient DCs show inhibited migration to the lymph nodes (LN) in response to CCR7, which was correlated with reduced DC numbers in LNs [10]
Summary
PI3Ks are activated by diverse signaling pathways including small G proteins of Ras and Rac family, tyrosine kinases- or G-protein- coupled receptors [1]. Studies using genetic and pharmacological targeting of PI3Kδ isoform has shown PI3Kδ is a homeostatic regulator of activation, downstream of MalMyD88-coupled TLR2 and TLR4 signaling pathways in DCs. PI3Kδ achieves this by dampening pro-inflammatory cytokine secretion, while supporting production of IL-10 [8].
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