Directing leukocyte polarization and migration by the phosphoinositide transfer protein TIPE2

Leukocyte polarization toward chemoattractants is essential for directed leukocyte migration, or chemotaxis. How leukocytes acquire polarity upon encountering chemical gradients is not well understood. We report here that leukocyte polarity is generated by TIPE2 (TNFAIP8L2), a transfer protein of phosphoinositide second messengers. TIPE2 functioned as a local enhancer of phosphoinositide-dependent signaling and cytoskeleton remodeling, promoting leading edge formation. Conversely, TIPE2 acted as an inhibitor of the GTPase Rac, promoting trailing edge polarization. Consequently, TIPE2-deficient leukocytes were defective in polarization and chemotaxis, and TIPE2-deficient mice were resistant to leukocyte-mediated neural inflammation. Thus, the leukocyte polarizer is a dual-role phosphoinositide transfer protein, and a potential therapeutic target for treating inflammatory diseases.