Platelet-derived chemokines: pathophysiology and therapeutic aspects

Abstract

The identification of chemokines in blood platelets has strengthened our view of these cells as participants in immune host defense. Platelet chemokines representing prestored and rapidly releasable proteins may play a major role as first-line inflammatory mediators. This is evident from their capability to recruit early inflammatory cells such as neutrophil granulocytes and monocytes and even to exhibit direct antimicrobial activity. However, insight is growing that platelet chemokines may be also long-term regulators, e.g., by activating T lymphocytes, by modulating the formation of endothelium and even thrombocytopoiesis itself. This review deals with the individual and cooperative functionality of platelet chemokines, as well as their potential as a basis for therapeutic intervention in the pathology of inflammation, infection, allergy and tumors. Within this context, therapeutic strategies based on the use of antibodies, modified chemokines, chemokine-binding proteins and chemokine receptor antagonists as well as first clinical studies will be addressed.

Fig. 1

Roles of major platelet-derived chemokines in the recruitment of blood leukocytes and the regulation of megakaryocytopoiesis and angiogenesis. Following the formation of a thrombus at an injured vessel wall, activated platelets rapidly secrete CXCL4, CCL5 and PBP/CTAP-III, two precursors of the active CXCL7 chemokine NAP-2. Following processing of these precursors by thrombus-associated neutrophils (PMN), i.e., in an environment depleted of protease inhibitors, the arising NAP-2 cooperates with CXCL4 in negative regulation of megakaryocytopoiesis, thus counter-acting CXCL12, an inducer of TPO. Both CXCL12 and NAP-2 participate in stimulating angiogenesis, while CXCL4 and especially CXCL4L1 represent strong inhibitors of angiogenesis. Although not chemotactic itself, CXCL4 cooperates with NAP-2 and CCL5 in recruiting PMN and monocytes (Mo), respectively, to the vessel wall. Both CCL5 and CXCL4 also induce adherence of eosinophils (Eo), while CCL5 recruits T cells (T). Transmigration of the cells is stimulated by extravascular NAP-2 (PMN) and CCL5 (Mo, Eo, T)