The longevity-associated BPIFB4 gene guarantees vascular homeostasis and immune protection through platelets

Geroscience. 2024 Jun 17. doi: 10.1007/s11357-024-01242-9. Online ahead of print.

Abstract

Beyond their activity in hemostasis and thrombosis, recent advances attribute platelets a pro-youthful role capable to attenuate immune senescence and age-related neuroinflammation. Previous studies from our group associated a polymorphic haplotype variant in the BPIFB4 gene (LAV-BPIFB4) with exceptional longevity. Transfer of the LAV-BPIFB4 in preclinical models has proved strategic to cope with frailty conditions, aging-related events, e.g., cardiovascular ones, and immune dysfunction mainly through a favorable conditioning of the immune system. However, whether platelets participate in LAV-BPIFB4 therapeutic action is currently unknown. Herein, we discovered that platelets were instrumental in boosting the favorable health outcomes of the systemic AAV-LAV-BPIFB4 gene transfer in vivo, as the α-CD42b platelet depletion completely abolished the vascular protective action of LAV-BPIFB4 and suppressed its pro-resolutive CD206 + anti-/CD86 + pro-inflammatory Ly6C + monocyte skewing to LPS stimulation. Of note, this is associated with a huge drop in the protective levels of BPIFB4 in the plasma of AAV-LAV-BPIFB4-injected C57BL/6 mice, indicating that plasma circulating platelets may be a reservoir of the BPIFB4 protein. Indeed, we noticed that BPIFB4 was released by human platelets, a process that is amplified in LAV-allele carrier donors. Accordingly, lentivirus-mediated overexpression of human LAV-BPIFB4 isoform, but not WT-BPIFB4 isoform was able in leading differentiated megakaryocytes to release more platelet-like-particles enriched for BPIFB4. In addition, in vitro, the M2 macrophage polarization increased when releasate from platelets, and even more from LAV pre-stimulated once, was added in monocyte cell culture. Our data suggest that platelet release of BPIFB4 and of yet-to-be-determined unidentified factors mediates the therapeutic efficacy of LAV-BPIFB4 treatment.

Keywords: BPIFB4 gene; Platelets; Vascular homeostasis.