GPVI and Thromboxane Receptor on Platelets Promote Proinflammatory Macrophage Phenotypes during Cutaneous Inflammation

Abstract

Platelets are well known for their role in hemostasis but are also increasingly recognized for their supporting role in innate immune responses. Here, we studied the role of platelets in the development of peripheral inflammation and found that platelets colocalize with macrophages in the inflamed tissue outside of blood vessels in different animal models for cutaneous inflammation. Collagen-treatment of macrophages isolated from paws during zymosan-induced inflammation induced thromboxane synthesis through the platelet-expressed collagen receptor glycoprotein VI. Deletion of glycoprotein VI or its downstream effector thromboxane A2 receptor (TP) reduced zymosan-induced mechanical allodynia without altering macrophage recruitment or formation of macrophage/platelet complexes. Instead, macrophages in inflamed paws of glycoprotein VI- and TP-deficient mice exhibited an increased expression of anti-inflammatory markers and synthesized less proinflammatory mediators (prostaglandin E and IL6). TP expression on platelets was necessary to mediate increased prostaglandin E and IL6 synthesis, whereas TP expression on macrophages was sufficient to decrease the expression of the anti-inflammatory macrophage marker CD206, showing that TP activation on platelets and macrophages regulates different aspects of macrophage activation.

Platelet “first responders” in wound response, cancer, and metastasis

“…GPVI is a major collagen receptor that recognizes the quaternary structure of collagen, and activates platelets [60,61]. Platelet GPVI monomers shift from low affinity and signal transduction potential to multimers that gain high affinity collagen periodic structure [41,62–65]. …”

Activated Platelets Induce an Anti-Inflammatory Response of Monocytes/Macrophages through Cross-Regulation of PGE2and Cytokines

“…Most platelet functions and their interactions with other cell types are restricted to events taking place within the blood vessels. Recently, we found that platelets colocalize with macrophages outside of the blood vessels in several models for cutaneous inflammation and suppress the expression of anti-inflammatory markers and enhance the synthesis of proinflammatory mediators in the associated macrophages [5]. Monocytes in the bloodstream and macrophages in tissues play central roles in various immunological reactions.…”

“…Notably, platelets store in granules a wide variety of signaling factors (e.g., mitogenic and angiogenic factors, chemokines (i.e., CXCL4), serotonin, histamine, nucleotides, and proteases), which are released upon platelet activation and have the potential to induce or to modulate proinflammatory responses of macrophages [21]. In addition, platelets are able to synthesize lipid mediators like thromboxane A2 (TXA2) [5, 22, 23] or PGE 2 [24, 25] upon activation. Furthermore, platelets have been shown to convert human peripheral blood circulating monocytes to IL-10-producing regulatory monocytes [26].…”

Myc binding protein 2 suppresses M2‐like phenotypes in macrophages during zymosan‐induced inflammation in mice

“…3D). Interestingly, this time frame corresponds with the appearance of monocyte-derived macrophages in the inflamed tissue during zymosan-induced inflammation [25,27].…”