Regulation of Neutrophil Adhesion and Immune Response: Influence of ATP, Adenosine, and Iodoacetic Acid

Neutrophils, key effector cells of the innate immune system, infiltrate infected tissues, adhere to them, and destroy pathogens by releasing the bactericidal content of intracellular granules and producing reactive oxygen species (ROS) and nitric oxide (NO). However, these aggressive antimicrobial products of neutrophil secretion can damage surrounding tissues and initiate inflammation. Adenosine, which is produced in excess by damaged tissues, is known to limit the neutrophil immune response and suppress inflammation, acting primarily through adenosine receptors. We compared the effects of ATP, adenosine, and iodoacetic acid (IAA), an inhibitor of glycolysis, on neutrophil adhesion to fibronectin and accompanying secretion of free amino acids, proteins, ROS, and NO. Our results indicate that the immunosuppressive effect of adenosine is unlikely to be due to the inhibition of oxidative stress or protein secretion. Neither ATP nor adenosine altered ROS and NO production during neutrophil adhesion, whereas IAA suppressed it. ATP did not affect the composition of secreted proteins, while adenosine stimulated the release of aggressive components of primary granules. We also investigated previously undescribed dynamics of secretion of the amino acid hydroxylysine by neutrophils during adhesion: ATP stimulated, while adenosine and IAA selectively and strongly inhibited hydroxylysine release. Hydroxylysine is a product of lysyl hydroxylase (LH), whose expression and activity positively correlate with cell invasiveness and metastatic potential of various types of tumor cells. Given the similarities between neutrophils and tumor cells in energy metabolism and invasive capacity, we hypothesize that adenosine and IAA may suppress immune responses by inhibiting neutrophil infiltration into tissues through selective blocking of LH activity/hydroxylysine release. Further studies are required to directly test this hypothesis.