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.

除了它们在止血和血栓形成中的活性外，最近的进展还认为血小板具有促进青年的作用，能够减轻免疫衰老和与年龄相关的神经炎症。我们小组以前的研究将 BPIFB4 基因 （LAV-BPIFB4） 中的多态性单倍型变异与非凡的寿命联系起来。事实证明，LAV-BPIFB4 在临床前模型中的转移主要通过免疫系统的良好调节来应对虚弱状况、衰老相关事件（例如心血管事件）和免疫功能障碍具有战略意义。然而，血小板是否参与 LAV-BPIFB4 治疗作用目前尚不清楚。在此，我们发现血小板有助于促进体内全身性 AAV-LAV-BPIFB4 基因转移的良好健康结果，因为 α-CD42b 血小板耗竭完全消除了 LAV-BPIFB4 的血管保护作用并抑制了其促果断 CD206 + 抗-/CD86 + 促炎性 Ly6C + 单核细胞偏向 LPS 刺激。值得注意的是，这与注射 AAV-LAV-BPIFB4 的 C57BL/6 小鼠血浆中 BPIFB4 保护水平的大幅下降有关，表明血浆循环血小板可能是 BPIFB4 蛋白的储存库。事实上，我们注意到 BPIFB4 是由人类血小板释放的，这一过程在 LAV 等位基因载体供体中被扩增。因此，慢病毒介导的人 LAV-BPIFB4 亚型过表达，而不是 WT-BPIFB4 亚型的过表达，能够引导分化的巨核细胞释放更多富含 BPIFB4 的血小板样颗粒。此外，在体外，当从血小板中释放出时，M2 巨噬细胞极化增加，在单核细胞培养物中加入一次预刺激的 LAV 中，M2 巨噬细胞极化增加。 我们的数据表明，BPIFB4 的血小板释放和尚未确定的未确定因子介导了 LAV-BPIFB4 治疗的治疗效果。