The signaling role of CD40 ligand in platelet biology and in platelet component transfusion

Abstract

The CD40 ligand (CD40L) is a transmembrane molecule of crucial interest in cell signaling in innate and adaptive immunity. It is expressed by a variety of cells, but mainly by activated T-lymphocytes and platelets. CD40L may be cleaved into a soluble form (sCD40L) that has a cytokine-like activity. Both forms bind to several receptors, including CD40. This interaction is necessary for the antigen specific immune response. Furthermore, CD40L and sCD40L are involved in inflammation and a panoply of immune related and vascular pathologies. Soluble CD40L is primarily produced by platelets after activation, degranulation and cleavage, which may present a problem for transfusion. Soluble CD40L is involved in adverse transfusion events including transfusion related acute lung injury (TRALI). Although platelet storage designed for transfusion occurs in sterile conditions, platelets are activated and release sCD40L without known agonists. Recently, proteomic studies identified signaling pathways activated in platelet concentrates. Soluble CD40L is a good candidate for platelet activation in an auto-amplification loop. In this review, we describe the immunomodulatory role of CD40L in physiological and pathological conditions. We will focus on the main signaling pathways activated by CD40L after binding to its different receptors.

Figure 1

Sheme of the CD40 ligand gene structure and its different isoforms. Intracellular domain (IC), transmembrane domain (TM), extracellular domain (EC).

Figure 2

CD40L and its receptors: the binding of CD40L to CD40, αIIbβ3, α5β1, or Mac-1 (αMβ2) induces different inflammatory pathologies. Systemic lupus erythematosus (SLE), transfusion-related acute lung injury (TRALI), reactive oxygen and nitrogen species (RONS), Myeloperoxidase (MPO).

Figure 3

Schematic overview of the regulation of platelet CD40L and the role of sCD40L in signaling after binding to platelet CD40 and αIIbβ3 inducing an auto-amplification loop. Synaptosomal-associated protein 23 (SNAP23), mitogen-activated protein kinase (MAPK), nuclear factor kappa B (NF-κB), protein kinase B (AKT) matrix metalloproteinase-2 (MMP-2), TNF receptor associated factor 2 (TRAF2).

Figure 4

Principal signaling pathways inducing platelet activation in platelet components. Phosphoinositide 3-kinase (PI3K), mitogen-activated protein kinase (MAPK), protein kinase B (AKT), Thromboxane A2 (TxA2), Vasodilator-stimulated phosphoprotein (VASP), Ras-proximate-1 (Rap1), Heat shock protein 27 (HSP27).