Platelet-derived Integrin- and Tetraspanin-enriched Tethers as key effectors in thrombo-Inflammation

Introduction

Platelets are mediators of haemostasis and thrombosis, but are also increasingly recognized as versatile effector cells of innate immunity. The concept of thrombo-inflammation recognizes that thrombotic and inflammatory pathomechanisms are closely intertwined.

Role of Platelets

Platelets act as central orchestrators of:

• Immune cell trafficking
• Vascular barrier function
• Organ integrity

They contribute to organ injury in severe disorders with limited treatment options, such as stroke, sepsis, and ARDS. The underlying molecular mechanisms are not known.

Novel Effector Mechanism

I recently discovered an unexpected novel effector mechanism in platelets with potentially huge impact for understanding these cells in health and disease. Resting platelets can rapidly reorganize the entire pool of their principal adhesion receptor, integrin αIIbβ3, along with its associated tetraspanins and signalling machinery into 'disintegration' complexes (DISCs) in distinct membrane microdomains.

Function of DISCs

These DISCs serve as building blocks for a novel organelle, the 'Platelet-derived Integrin and Tetraspanin-enriched Tether' (PITT). PITTs are:

• Loaded with signalling molecules
• Contain ribosomes and RNA
• Capable of segregating from the platelet to promote thrombo-inflammation

Additionally, β1-integrins as well as glycoprotein (GP)VI can be integrated into DISCs and deposited at discrete adhesion points.

Hypothesis

I therefore postulate that circulating platelets have the capacity to use their principal adhesion/signalling machineries in two fundamentally different ways, thereby switching between the haemostatic and a thrombo-inflammatory effector programme. If proven correct, this would implicate a radically new paradigm in platelet biology and open new avenues for the treatment of a wide range of diseases with major societal impact.

Objectives of PITT-Inflame

PITT-Inflame will:

1. Provide a detailed molecular composition and architecture of DISCs and PITTs
2. Decipher underlying signalling networks
3. Identify PITT-induced effects on target cells
4. Deduce therapeutic strategies