PI3K signalling in inflammation

PI3Ks regulate several key events in the inflammatory response to damage and infection. There are four Class I PI3K isoforms (PI3K alpha,beta,gamma,delta), three Class II PI3K isoforms (PI3KC2 alpha, C2 beta, C2 gamma) and a single Class III PI3K. The four Class I isoforms synthesise the phospholipid 'PIP3'. PIP3 is a 'second messenger' used by many different cell surface receptors to control cell movement, growth, survival and differentiation. These four isoforms have overlapping functions but each is adapted to receive efficient stimulation by particular receptor sub-types. PI3K gamma is highly expressed in leukocytes and plays a particularly important role in chemokine-mediated recruitment and activation of innate immune cells at sites of inflammation. PI3K delta is also highly expressed in leukocytes and plays a key role in antigen receptor and cytokine-mediated B and T cell development, differentiation and function. Class III PI3K synthesises the phospholipid PI3P, which regulates endosome-lysosome trafficking and the induction of autophagy, pathways involved in pathogen killing, antigen processing and immune cell survival. Much less is known about the function of Class II PI3Ks, but emerging evidence indicates they can synthesise PI3P and PI34P2 and are involved in the regulation of endocytosis. The creation of genetically-modified mice with altered PI3K signalling, together with the development of isoform-selective, small-molecule PI3K inhibitors, has allowed the evaluation of the individual roles of Class I PI3K isoforms in several mouse models of chronic inflammation. Selective inhibition of PI3K delta, gamma or delta has each been shown to reduce the severity of inflammation in one or more models of autoimmune disease, respiratory disease or allergic inflammation, with dual gamma/delta or beta/delta inhibition generally proving more effective. The inhibition of Class I PI3Ks may therefore offer a therapeutic opportunity to treat non-resolving inflammatory pathologies in humans. This article is part of a Special Issue entitled Phosphoinositides. (C) 2014 The Authors. Published by Elsevier B.V.