The tumor necrosis factor (TNF)-α-induced protein 8-like 2 (TIPE2), predominantly expressed in bone marrow-derived cells or lymphoid tissues, is an essential regulator of immune homeostasis. TIPE2 acts as a key negative modulator of inflammatory signaling through the suppression of toll-like receptor (TLR) activity, with TIPE2-deficient mice exhibiting spontaneous systemic inflammation and premature death.