4-HNE reduces phagocytosis through the expression of Synaptotagmin 1 in human monocyte-derived macrophages

Reactive oxygen species (ROS) react with polyunsaturated fatty acids (PUFA) and generate the reactive aldehyde 4-hydroxynonenal (4-HNE). 4-HNE is a potent modulator of cell signaling, proliferation, and death. Our transcriptomics analysis revealed that upon treatment of human monocyte-derived macrophages with 4-HNE synaptotagmin-1 (SYT1), the main calcium sensor for neurotransmitter release, became the most strongly upregulated protein. This is surprising, as SYT1 expression is normally restricted to neurons and neuroendocrine cells. Using overexpression of SYT1 fused to a fluorescent reporter protein, we found SYT1 predominantly locates at the plasma membrane in macrophages. Based on this finding, and on the reported roles of other SYT forms in macrophages and other immune phagocytes, we tested the role of SYT1 in phagocytosis. Functional assays showed that SYT1 inhibited phagocytosis of pathogenic bacteria. Thus, our findings reveal an unexpected role of SYT1 in immune cells.