Thioredoxin-interacting protein, hematopoietic stem cells, and hematopoiesis

Reactive oxygen species (ROS) can regulate diverse signaling pathways and functions in hematopoietic cells. Thioredoxin-interacting protein (TXNIP) plays an important role in mammalian cells by inhibiting thioredoxin (TRX) under oxidative stress conditions. TXNIP is expressed in hematopoietic stem cells (HSCs), and its expression decreases as HSCs differentiate into precursor cells. However, this reduction in expression does not sufficiently explain the function of TXNIP in hematopoietic cells under oxidative stress conditions. Here, we review how ROS can regulate hematopoiesis by focusing on the function of TXNIP in hematopoietic cells under oxidative stress conditions.

Studies of Txnip mice have demonstrated an antioxidant function of TXNIP in hematopoietic cells or immune cells. This antioxidant function differs from the conventional pro-oxidant activity of TXNIP observed in other cell types under oxidative stress. The data suggest a context-dependent function of TXNIP under oxidative stress conditions and, in particular, a differential function of TXNIP in hematopoietic cells via its direct interaction with other redox regulatory proteins.

The regulation of ROS is important in determining cellular fate decisions. TXNIP acts as a negative regulator of TRX via direct interaction, and it increases the levels of ROS under oxidative stress. However, TXNIP has an antioxidant function in hematopoietic cells or immune cells, as ROS levels are elevated and induce apoptosis in Txnip hematopoietic cells. These results suggest that the amount of TXNIP is inversely associated with ROS levels, and the loss of TXNIP can increase ROS levels in immune cells or hematopoietic cells.