Abstract
BackgroundMacrophages are the dominant phagocyte at sites of wound healing and inflammation, and the cellular and acellular debris encountered by macrophages can have profound effects on their inflammatory profile. Following interaction with apoptotic cells, macrophages are known to switch to an anti-inflammatory phenotype. Activated platelets, however, are also a major component of inflammatory lesions and have been proposed to be pro-inflammatory mediators. In the present study, we tested the hypothesis that macrophage interaction with activated platelets results in an inflammatory response that differs from the response following phagocytosis of apoptotic cells.MethodsHuman monocyte-derived macrophages (hMDMs) were co-incubated with autologous activated platelets (AAPs) and the platelet-macrophage interaction was examined by electron microscopy and flow cytometry. The cytokines TNF-α, IL-6, and IL-23 were also measured during LPS-activated hMDM co-incubation with AAPs, which was compared to co-incubation with apoptotic lymphocytes. Cytokine secretion was also compared to platelets pre-treated with the gluococorticoid dexamethasone.ResultsMacrophages trapped and phagocytized AAPs utilizing a mechanism that was significantly inhibited by the scavenger receptor ligand fucoidan. LPS-induced macrophage secretion of TNF-α, IL-6, and IL-23 was inhibited by co-incubation with apoptotic cells, but enhanced by co-incubation with AAPs. The platelet-dependent enhancement of LPS-induced cytokines could be reversed by pre-loading the platelets with the glucocorticoid dexamethasone.ConclusionsThe interaction of human macrophages with autologous platelets results in scavenger-receptor-mediated platelet uptake and enhancement of LPS-induced cytokines. Therefore, the presence of activated platelets at sites of inflammation may exacerbate pro-inflammatory macrophage activation. The possibility of reversing macrophage activation with dexamethasone-loaded platelets is a promising therapeutic approach to treating unresolved inflammation.
Highlights
Macrophages are the dominant phagocyte at sites of wound healing and inflammation, and the cellular and acellular debris encountered by macrophages can have profound effects on their inflammatory profile
Macrophage Phagocytosis of Autologous Platelets To examine the interaction between human MDMs and autologous platelets, we utilized an in vitro co-culture system consisting of 7-day old Human monocyte-derived macrophages (hMDMs) to which we added freshly isolated autologous platelets
The use of autologous platelets excludes the possibility that platelet-macrophage interactions are the result of an immune response triggered by the recognition of platelets as ‘foreign.’ The hMDMs and platelets were first co-cultured in serum-free RPMI media and examined by scanning electron microscopy (SEM) and TEM at various time points to visualize the interaction between these two different cell types
Summary
Macrophages are the dominant phagocyte at sites of wound healing and inflammation, and the cellular and acellular debris encountered by macrophages can have profound effects on their inflammatory profile. The importance of phagocytosis in the resolution of inflammation is emphasized by pathological conditions involving impaired phagocytosis, which may manifest as persistent infections or chronic inflammatory lesions such as diabetic ulcers and atherosclerotic plaques [7,8,9,10,11]. During their differentiation from primary monocytes, macrophages acquire specialized receptors and machinery for recognizing and clearing both apoptotic and infected cells [12]. These changes in the platelet membrane may provide molecular signals to macrophages that trigger phagocytosis, the precise mechanism by which macrophages recognize and phagocytose activated platelets remains to be identified
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