Graphical Abstract Highlights d Pore-forming agents evoke calcium-dependent lipid scrambling in the plasma membrane d This effect promotes plasma membrane repair and is mediated by lipid scramblase TMEM16F d TMEM16F induces repair by facilitating release of extracellular vesicles d TMEM16F-deficient mice display greater susceptibility to Listeria monocytogenes

Melatonin is a hormone that has immunomodulatory activity and is believed to influence the production of antibodies in mammals. The aim of the present study was to investigate the effect of suppressed melatonin synthesis on the antibody production. BALB/c mice were immunized with T-cell-dependent (TD) and T-cell-independent (TI) antigens and kept under (i) normal lighting, (ii) constant exposure to light, (iii) exposed to light and treated daily with melatonin. It was revealed that melatonin modulated TD and TI antibody production. Suppressed melatonin synthesis increased the amount of IgM, IgG1, IgG2b and IgG3 antibodies after immunization with TI antigen. The level of TD antibodies IgM, IgG2a, IgG2b and IgG3 also increased, however, the antigen-specific antibodies of IgG1 isotype significantly decreased in mice exposed to light. Daily melatonin treatment brought the antibody level back to normal. The antibody concentration in the sera of mice kept at normal lighting was significantly higher when the immunizations were performed in the evening. The action of melatonin on B cells via MT2 receptor was shown in vitro and in vivo.

Neutrophils are cells of the innate immune system that first respond and arrive to the site of infection. Melatonin modulates acute inflammatory responses by interfering with leukocyte recruitment. It is known that melatonin modulates granulocyte migration though the endothelial layer thereby acting on the endothelial cell. Here we investigated whether melatonin could modulate granulocyte infiltration by acting directly on granulocytes. Granulocyte infiltration into the peritoneal cavity was investigated in mice kept at normal light/dark conditions and mice kept under constant lighting. To induce migration of neutrophils from the blood into the injury site via the endothelial layer, a bacterial product N-formyl-l-methionyl- l-leucyl- l-phenylalanine (fMLP) was injected into the peritoneal cavity. We found that the number of infiltrated granulocytes during the dark time was lower than that during the light time. It did not depend on circadian time. Moreover, the expression of an adhesion molecule, CD18, on granulocytes, was also lower during the dark time as compared with the light time. We have found that melatonin inhibited fMLP-induced CD18 up-regulation. Importantly, melatonin also inhibited the integrin-mediated granulocyte adhesion to intercellular adhesion molecule-coated plates. This study additionally showed that melatonin receptors MT2 and MT3/quinone reductase 2 (QR2) are expressed on granulocytes. Interestingly, melatonin increases the expression of its MT3/QR2 receptor. The fMLP-mediated CD18 up-regulation was inhibited by melatonin via MT2 receptor and the integrin-mediated granulocyte adhesion was inhibited by melatonin via MT3/QR2 and MT2 receptors. In conclusion, we show that melatonin suppresses granulocyte migration via endothelium by acting directly on granulocytes.

Circadian rhythmicity and melatonin secretion influence many functions in mammals, including the immune system function. The aim of our study is to investigate the effect of suppression of melatonin synthesis (caused by constant lighting) on the quantity of leucocytes in immunized BALB/c mice. The mice were kept under different lighting conditions: (1) customary environmental lighting; (2) constant exposure to light; (3) exposure to light and daily melatonin treatment. The disrupted melatonin synthesis had no effect on the number of cells in the thymus, bone marrow, spleen, lymph nodes and Peyer's patches of immunized mice. However, the mice kept under constant light had an increased number of leucocytes in the peritoneal cavity when immunizations were performed in the evening. Melatonin treatment normalized the cell number. When the immunizations were performed in the morning, the numbers of cells in peritoneum of mice kept under constant lighting conditions were lower compared to mice exposed to normal lighting conditions. The number of cells of mice kept in normal light/dark conditions was significantly higher when the immunizations were performed in the morning. The number of peritoneal cells, however, did not depend on the immunization time when mice were kept under constant lighting. In conclusion, the amount of peritoneal cells in mice immunized with T cell-dependent antigens seems to be related to circadian rhythmicity, melatonin production and immunization timing.

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