On the mechanism of apoptosis-inducing activity of human calprotectin: Zinc sequestration, induction of a signaling pathway, or something else?

SummaryCalprotectin, a heterodimer present in neutrophil cytoplasm, has antimicrobial and apoptosis-inducing activities. At the moment, there are two general hypotheses about the mechanism of action of calprotectin: (i) exclusion of extracellular zinc by calprotectin, and consequently induction of apoptosis; (ii) binding of calprotectin to a cell membrane receptor, and consequently, activation of a signaling pathway for apoptosis. Here, we introduce another hypothesis, i.e. inhibition or destruction of “target” inside cells. We suggest that calprotectin might become internalized non-specifically, maybe in a process like pinocytosis. This process is probably independent of the zinc concentration. We also demonstrated that the internal target hypothesis successfully predicts cell survival behavior of cultured cells as a function of calprotectin concentration. Additional analyses should be performed to elucidate the real calprotectin “target”.