Platelet-derived β2m regulates age related monocyte/macrophage functions

Abstract

Platelets have central roles in both immune responses and development. Stimulated platelets express leukocyte adhesion molecules and release numerous immune modulatory factors that recruit and activate leukocytes, both at the sites of activation and distantly. Monocytes are innate immune cells with dynamic immune modulatory functions that change during the aging process, a phenomenon termed "inflammaging". We have previously shown that platelets are a major source of plasma beta-2 microglobulin (β2M) and that β2M induced a monocyte pro-inflammatory phenotype. Plasma β2M increases with age and is a pro-aging factor. We hypothesized that platelet derived β2M regulates monocyte phenotypes in the context of aging. Using wild-type (WT) and platelet specific β2M knockout mice (Plt-β2M-/-) mice, we found that plasma β2M increased with age and correlated with increased circulating Ly6C Hi monocytes. However, aged Plt-β2M-/mice had significantly fewer Ly6C Hi monocytes compared to WT mice. Quantitative real-time PCR of circulating monocytes showed that WT mouse monocytes were more "pro-inflammatory" with age, while Plt-β2M-/derived monocytes adopted a "pro-reparative" phenotype. Older Plt-β2M-/mice had a significant decline in heart function compared to age matched WT mice, as well as increased cardiac fibrosis and pro-fibrotic markers. These data suggest that platelet-derived β2M regulates age associated monocyte polarization, and a loss of platelet derived β2M shifted monocytes and macrophages to a pro-reparative phenotype and increased pro-fibrotic cardiac responses. Platelet regulation of monocyte phenotypes via β2M may maintain a balance between inflammatory and reparative signals that affects age related physiologic outcomes.

β2M Signals Monocytes Through Non-Canonical TGFβ Receptor Signal Transduction

“…Conversely, IL-4, IL-13, IL-10, TGF-β1, M-CSF induce pro-reparative monocyte and macrophage polarization 8,9,11 . We previously demonstrated that platelet derived beta-2 microglobulin (β2M) induced an inflammatory monocyte phenotype 12,13 , and now expand our findings to demonstrate that monocyte phenotype and polarization is in part driven by plasma β2M and TGFβ ratios in vivo. Platelets are the major plasma source of both β2M and TGFβ and platelet derived β2M inflammatory phenotype is opposed by TGFβ 12 .…”

“…Our previous work showed that β2M and TGFβ are important for monocyte phenotype responses in the context of both acute myocardial infarction and aging 12,34 . Our understanding of how monocytes change immune functions in the circulation and its impact on tissue injury and aging responses are poorly understood.…”

“…All mice used in these experiments were on a C57BL6/J background. Mice were between 4 and 8 weeks old at the time of experiment to study age independent effects, as we have shown age influences monocyte phenotype 13 . Male and female mice were used in our experiments as we have previously shown no difference between genders in our mouse model 12 .…”

“…Group size of animals were determined from previously performed experiments under similar conditions 12,13 . Wild-type mice were obtained from Jackson Laboratory (000664) and the generation of PF4Cre-β2M Flox/Flox mouse line has been previously described 12 .…”

Association Between Monocyte Levels and Breast Lump Detected By Ultrasound Among Chinese Women: A Longitudinal Study

“…Furthermore, data suggested that the total number of immune cells does not change between younger (< 40 years) and middle-aged (40-60 years) groups, but it signi cantly decreased at an older age (>60 years) [33]. The decreased levels of immune cells, especially platelet-derived beta-2 microglobulin, shifts monocytes and macrophages to a pro-reparative phenotype and reduce the risk of pro-brotic responses [34].…”