2026-09-18 ミュンヘン大学（LMU）
＜関連情報＞
- https://www.lmu.de/en/newsroom/news-overview/news/how-the-spleen-regulates-the-proportion-of-activated-platelets-in-the-blood-f6eeaae2.html
- https://www.science.org/doi/10.1126/science.aec7230
脾臓による全身性血小板活性化状態の調節 Splenic regulation of systemic platelet activation state
Lisa Laun, Alexander Leunig, Felix Zhang, Sezer Akgöl, […] , and Leo Nicolai
Science Published:17 Sep 2026
DOI:https://doi.org/10.1126/science.aec7230
Structured Abstract
INTRODUCTION
Platelets are critical in hemostasis as they prevent bleeding by rapidly sealing damaged blood vessels. They are therefore built to acutely switch from a calm, quiescent state to an active state in the vasculature. This sensitivity is essential for vascular integrity but carries a cost: Activated platelets circulating in the blood are known to contribute to heart attacks, strokes, and tissue damage during infection, and protective mechanisms that limit systemic platelet activation are poorly characterized.
RATIONALE
Blood cells normally remain within blood vessels, shielded from tissue components that could trigger unwanted activation. The spleen is distinct as blood cells leave the vessels entirely in the red pulp and pass slowly through tissue before reentering the circulation. We reasoned that this unusual anatomy might allow the spleen to inspect passing platelets and selectively remove those that are overactive, while letting quiescent platelets pass through. We tested this idea, investigating the effects of splenic platelet clearance in disease models and uncovering the molecular signals that would allow the spleen to selectively remove activated platelets.
RESULTS
Using intravital imaging and transfusion models in mice, we found that platelets activated by thrombosis or inflammatory signals were captured and removed by the spleen far more efficiently than quiescent platelets. Blocking this splenic filter—either by removing the spleen or by temporarily cutting off its blood supply—enhanced thrombosis, lung injury, and pulmonary embolism in murine disease models. Examining tissues from patients and conducting cellular imaging in heart attack patients, we found matching evidence that the human spleen also enlarges and accumulates activated platelets under these conditions, indicating that the same protective system operates in humans.
We found that in mice, platelets passing through the splenic red pulp encountered extracellular matrix proteins that triggered activating signals in the platelets. At the same time, a separate inhibitory surface receptor, G6b, delivered a counteracting signal that normally keeps this activation in check, allowing healthy platelets to reenter the bloodstream. However, platelets that arrived already overactivated—for instance, after a clotting event—were not restrained by the inhibitory signal. Instead, their activation signal dominated and triggered integrin engagement and arrest in the spleen, marking them for permanent removal by spleen-resident scavenger cells.
CONCLUSION
These findings revealed that the spleen continuously monitors the activation state of circulating platelets, filtering out overactive cells while sparing quiescent platelets. This potentially explains long-standing clinical observations that patients without a spleen face higher risks of clotting and death due to hyperinflammation. The identified signaling axes could represent new targets for therapies aimed at lowering platelet activation under conditions such as heart attack, stroke, and sepsis, in which excess platelet activity drives disease severity.
(Left) In the steady state, circulating platelets remain quiescent. Upon an activating stimulus, a subset of platelets becomes activated. (Right) In the splenic red pulp, platelets encounter extracellular matrix components that provide both activating and inhibitory signals: Glycoprotein VI ligands trigger activation, whereas G6b-B, binding perlecan, maintains quiescence and enables recirculation. In activated platelets, activation signals are integrated and inhibitory signaling is overridden, resulting in integrin activation and splenic retention.
Abstract
Platelets are essential to prevent blood loss and to orchestrate inflammation. Thrombotic complications of vascular disease and hyperresponsive platelets are associated with adverse outcomes, yet physiological mechanisms counteracting systemic platelet activation are poorly defined. In mice, we found that the spleen filters activated platelets in thrombotic and inflammatory conditions, limiting pathology by maintaining platelet quiescence. Glycoprotein VI–dependent activation of platelets initiated by extracellular matrix components in the splenic red pulp was counterbalanced by G6b-B–immunoreceptor tyrosine-based inhibitory motif signaling triggered by perlecan in quiescent platelets, allowing them to recirculate. By contrast, threshold activation signals in preactivated platelets could override inhibition, leading to splenic capture through inside-out signaling and β1-integrin engagement. Thus, the spleen acts as a modulator of platelet responsiveness and thrombo-inflammatory risk.
