In npj Aging, researchers have described how immune cell infiltration in inflammaging can be reduced with an immune-related peptide in a mouse model.
Immune cell infiltration
In a previous paper, these researchers have reported that aging affects the movement of white blood cells (leukocytes) in a way that harms the immune system’s protective abilities [1]. That paper named cellular senescence and its secreted inflammatory molecules as causative factors that lead to more permeable vascular walls, thus causing white blood cells to more readily infiltrate into the peritoneal cavity of the abdomen.
While the dynamics of some white blood cells, such as neutrophils, have been better documented [2], the behavior of T cells and B cells has been less clear. Previous work has found that PEPITEM, a peptide related to immune system function, stimulates the production of spingosine-1-phosphate (S1P), which inhibits the transmission of white blood cells into tissues [3]. Therefore, these researchers employed a mouse model of peritonitis, the inflammation of the abdominal lining, in order to determine how PEPITEM influences white blood cells in differently aged animals.
Not all cells behave the same
The researchers administered zymosan to populations of 3-month-old and 21-month mice in order to induce peritoneal inflammation, and in some groups, they administered PEPITEM to combat it. As expected, in both young and old mice, the number of activated T cells, as measured by the CD45 marker, was increased with zymosan and decreased with PEPITEM. Naive and central memory T cells showed the same behaviors in young and old animals: greatly increased with zymosan and ameliorated with PEPITEM.
However, this did not occur among all cell populations. Cells that were positive for both KLRG1, which is a marker of terminal cell differentiation, and the T cell activator CD3 did not appear in the younger mice but appeared in the older ones. These cells were suppressed by PEPITEM.
Effector memory cells, on the other hand, were only suppressed by PEPITEM in younger mice, but not older mice. In younger mice, CD19+ B cells were increased with inflammation and suppressed by PEPITEM, but their levels were unaffected either way in older animals. Most critically, and perhaps most promising as a treatment, B cells that had markers specific to age were increased in both younger and older animals in response to zymosan and were suppressed by PEPITEM.
Taken together, these data suggest that PEPITEM can control the magnitude of an inflammatory response even in the ageing micro-environment, where low-grade chronic inflammatory phenotypes normally prevail and hinder efficient resolution.
Human cells
The researchers then tested two different groups of white blood cells: some were taken from donors under 40, while others were taken from donors over 65. Both of these populations adhered to endothelial cells that had been stimulated by cytokines, which is related to their migration and infiltration through the blood vessel walls. However, younger cells responded to adiponectin, and older cells did not; both populations, however, responded to PEPITEM.
The researchers note that due to differences in how males and females respond to inflammation, their research was exclusively on males. Further work, including both sexes and human trials, will need to be done to determine if PEPITEM can be used to combat the immune cell infiltration that accompanies inflammaging.
Literature
[1] Hopkin, S., Lord, J. M., & Chimen, M. (2021). Dysregulation of leukocyte trafficking in ageing: Causal factors and possible corrective therapies. Pharmacological Research, 163, 105323.
[2] Arnardottir, H. H., Dalli, J., Colas, R. A., Shinohara, M., & Serhan, C. N. (2014). Aging delays resolution of acute inflammation in mice: reprogramming the host response with novel nano-proresolving medicines. The Journal of Immunology, 193(8), 4235-4244.
[3] Chimen, M., McGettrick, H. M., Apta, B., Kuravi, S. J., Yates, C. M., Kennedy, A., … & Rainger, G. E. (2015). Homeostatic regulation of T cell trafficking by a B cell–derived peptide is impaired in autoimmune and chronic inflammatory disease. Nature medicine, 21(5), 467-475.
