Heterophilic interactions of platelet factor 4 and RANTES promote monocyte arrest on endothelium

Abstract

The chemokines platelet factor 4 (PF4) and RANTES (regulated on activation normal T cell expressed and secreted) are secreted by activated platelets and influence multiple cell types and biologic processes. For instance, PF4 inhibits progenitor cell proliferation and angiogenesis, while platelet-derived RANTES is involved in vascular recruitment of monocytes.

Novel uses for anti‐platelet agents as anti‐inflammatory drugs

“…This signalling may result in the upregulation of selectins and integrins on the surface of platelets , enabling platelets to bind and activate circulating leukocytes. A relationship between platelet P-selectin expression and platelet-leukocyte endothelial arrest after chemokine activation has since been revealed in several studies (Schober et al, 2002;Huo et al, 2003;Von Hundelshausen et al, 2005).…”

“…Indeed, exploiting mediators involved in platelet activation that are disease specific would obviously have advantages. Antagonists for specific chemokine receptors may be advantageous, for example the targeting of platelet CCR3 and CCR4 might be of benefit in treating asthmatics (Gonzalo et al, 1999;Sekiya et al, 2000), while the targeting of RANTES may be beneficial in the treatment of atherosclerosis since platelet-derived RANTES deposited on the surface of endothelial cells is necessary for monocyte accumulation (Von Hundelshausen et al, 2005). Indeed, RANTES receptor antagonists inhibit the infiltration of macrophages, and importantly, reduce neointima formation in ApoE-deficient mice (Schober et al, 2002;Huo et al, 2003).…”

Probing Functional Heteromeric Chemokine Protein–Protein Interactions through Conformation‐Assisted Oxime Ligation

“…While RANTES is a potent attractant of mononuclear cells, PF4 lacks classical chemo‐attractant functions 4. However, the presence of PF4 can synergistically enhance RANTES‐mediated cell‐recruitment mediated by heterophilic interactions between chemokines 4.…”

“…While RANTES is a potent attractant of mononuclear cells, PF4 lacks classical chemo‐attractant functions 4. However, the presence of PF4 can synergistically enhance RANTES‐mediated cell‐recruitment mediated by heterophilic interactions between chemokines 4. In fact, pharmacologic inhibition of RANTES and PF4 heterodimer formation inhibits monocyte recruitment and attenuates progression of atherosclerosis, lung injury, and aneurysm formation in mice 5.…”

“…A monolayer of endothelial cells was pre‐treated with chemokines or heterodimers, after which monocytes were passed over the surface 4. The presence of chemokines triggered monocyte arrest, and the number of arrested monocytes was recorded as measure of activity (Figure 5 A).…”