Neuropeptides as attractants of immune cells in the brain and their distinct signaling

Microglia, the immune cells of the central nervous system (CNS), are busy and vigilant housekeepers in the adult brain. The main candidate as a chemoattractant for microglia at damaged site is adenosine triphosphate (ATP). However, many other substances can induce immediate change of microglia. Some neuropeptides such as angiotensin II, bradykinin (BK), endothelin, galanin (GAL), and neurotensin are also chemoattractants for microglia. Among them, BK increased microglial migration via B₁ receptor with different mechanism from that of ATP. BK-induced migration was controlled by a G _i/o protein-independent pathway, while ATP-induced migration was via a G_i/o protein-dependent and also a mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK)-dependent pathway. On the other hand, GAL is reported to have a similar signal cascade as that of BK, though only part of the signaling was similar to that of BK-induced migration. For example, BK activates reverse-mode Na⁺/Ca²⁺ exchange allowing extracllular Ca²⁺ influx, while GAL induces intracellular Ca²⁺ mobilization via increasing inositol-1, 4, 5-trisphosphate. In addition, GAL activates MAPK/ERK-dependent signaling but BK did not. These results suggest that chemoattractants for immune cells in the brain including ATP and each peptide may have distinct role under both physiological and pathophysiological conditions.