Tnfaip8l2, also known as TIPE2, is a member of the tumor necrosis factor-α-induced protein 8 (TNFAIP8) family. It serves as a crucial negative regulator of both innate and adaptive immunity, playing a vital role in maintaining immune homeostasis by negatively regulating T cell receptor (TCR) and toll-like receptor (TLR) signal transduction [3]. It is also involved in the regulation of the RAC1-MTORC1 axis, which is related to autophagy, and the RHEB-MTORC1 pathway, which is associated with age-related hearing loss [1,2].

In Tnfaip8l2-deficient (Tnfaip8l2-/-) mouse models, features of oxidative stress in cochlear hair cells and age-related hearing degeneration were observed, similar to mTORC1-over-activated Tsc1-cKO mice. Rapamycin, an mTORC1 inhibitor, mitigated the hearing dysfunction caused by Tnfaip8l2-deficiency. Mechanistically, TNFAIP8L2 regulates mTORC1 signaling by inhibiting the GTPase activity of RHEB and RAC1 [2]. In an LPS-induced mouse endotoxemia model, TNFAIP8L2 deficiency exacerbated the inflammatory response and lung injury by controlling the MTOR activity [1].

In conclusion, Tnfaip8l2 is essential for maintaining immune homeostasis and regulating mTORC1-related biological processes. Gene-knockout mouse models have revealed its role in age-related hearing loss and endotoxemia-induced inflammatory responses, providing potential therapeutic targets for these diseases.