Regulation of neutrophil homeostasis by the TNFAIP8 family of polarity proteins.

The extremely short life span of neutrophils is critical for immune homeostasis and immune defense against pathogens, but the molecular mechanisms underlying this phenomenon are not fully understood. Here we report that TNFAIP8 (TNF-α-induced protein 8) family of polarity proteins regulates neutrophil homeostasis by propagating phosphoinositide signaling. Genetic deletion of two members of the TNFAIP8 family, i.e., TIPE0 and TIPE1, resulted in spontaneous neutrophilia and hepatitis. TNFAIP8 disruption preferentially increased the levels of two lipid second messengers, i.e., phosphatidylinositol 4,5-bisphosphate (PIP2) and phosphatidylinositol 3,4,5-trisphosphate (PIP3), in neutrophils. This subsequently led to suppression of AKT deactivation and increased neutrophil survival. Consequently, disruption of TNFAIP8 augmented infectious and chemical-induced neutrophil accumulation and damage. Therefore, these results suggest that TNFAIP8 controls neutrophil spontaneous death by regulating PIP2/PIP3 levels and promoting AKT deactivation in aging neutrophils. Modifying neutrophil death through this pathway provides a strategy and potential therapeutic target for infectious and inflammatory diseases.