Role of PI3Kδ and PI3Kγ in inflammatory arthritis and tissue localization of neutrophils

The p110δ isoform of class I phosphoinositide 3-kinase (PI3K) plays a major role in B cell receptor signaling, while its p110γ counterpart is thought to predominate in leukocyte chemotaxis. Consequently, emphasis has been placed on developing PI3Kγ selective inhibitors to treat disease states that result from inappropriate tissue accumulation of leukocytes. We now demonstrate that PI3Kδ blockade is effective in treating an autoimmune disorder in which neutrophil infiltration is required for tissue injury. Using the K/ BxN serum transfer model of arthritis, in which neutrophils and leukotriene B₄ (LTB₄) participate, we show that genetic deletion or selective inhibition of PI3Kδ diminishes joint erosion to a level comparable to its PI3Kγ counterpart. Moreover, the induction and progression of joint destruction was profoundly reduced in the absence of both PI3K isoforms and correlated with a limited ability of neutrophils to migrate into tissue in response to LTB₄. However, the dynamic interplay between these isoforms is not pervasive, as fMLP-induced neutrophil extravasation was primarily reliant on PI3Kγ. Our results not only demonstrate that blockade of PI3Kδ has potential therapeutic value in the treatment of chronic inflammatory conditions, but also provide evidence that dual inhibition of these lipid kinases may yield superior clinical results.