Calcium signaling and regulation of neutrophil functions: Still a long way to go

Neutrophils are the most abundant leukocytes in blood and disruption in their functions often results in an increased risk of serious infections and inflammatory autoimmune diseases. Following recent discoveries in their influence over disease progression, a resurgence of interest for neutrophil biology has taken place. The multitude of signaling pathways activated by the engagement of numerous types of receptors, with which neutrophils are endowed, reflects the functional complexity of these cells. It is therefore not surprising that there remains a huge lack in the understanding of molecular mechanisms underlining neutrophil functions. Moreover, studies on neutrophils are undoubtedly limited by the difficulty to efficiently edit the cell's genome. Over the past 30 years, compelling evidence has clearly highlighted that Ca²⁺ -signaling is governing the key processes associated with neutrophil functions. The confirmation of the role of an elevation of intracellular Ca²⁺ concentration has come from studies on NADPH oxidase activation and phagocytosis. In this review, we give an overview and update of our current knowledge on the role of Ca²⁺ mobilization in the regulation of pro-inflammatory functions of neutrophils. In particular, we stress the importance of Ca²⁺ in the formation of NETs and cytokine secretion in the light of newest findings. This will allow us to embrace how much further we have to go to understand the complex dynamics of Ca²⁺ -dependent mechanisms in order to gain more insights into the role of neutrophils in the pathogenesis of inflammatory diseases. The potential for therapeutics to regulate the neutrophil functions, such as Ca²⁺ influx inhibitors to prevent autoimmune and chronic inflammatory diseases, has been discussed in the last part of the review.