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Macrophage pro-inflammatory cytokine secretion is enhanced following interaction with autologous platelets
Christopher M Scull1, William D Hays, Thomas H Fischer
1Francis Owen Blood Research Lab, Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, 125 University Lake Rd, Chapel Hill, NC 27516, USA. cms2232@columbia.edu.
Background:
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. 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.
Methods:
Human 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.
Results:
Macrophages 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.
Conclusions:
The 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.
Insights
Activated platelets enhance pro-inflammatory responses in macrophages, unlike apoptotic cells. This platelet-induced inflammation can be reversed using dexamethasone-loaded platelets, offering a potential therapeutic strategy for unresolved inflammation.
Area of Science:
- Immunology
- Cell Biology
Background:
- Macrophages are key phagocytes in inflammation and wound healing.
- Interaction with apoptotic cells typically induces an anti-inflammatory macrophage phenotype.
- Activated platelets are present in inflammatory lesions and may promote inflammation.
Purpose of the Study:
- To investigate the inflammatory response of macrophages interacting with activated platelets.
- To compare this response to macrophage interaction with apoptotic cells.
Main Methods:
- Human monocyte-derived macrophages (hMDMs) were co-incubated with autologous activated platelets (AAPs).
- Platelet-macrophage interactions were analyzed using electron microscopy and flow cytometry.
- Cytokine secretion (TNF-α, IL-6, IL-23) was measured in LPS-activated hMDMs co-incubated with AAPs or apoptotic lymphocytes, and with dexamethasone-pre-treated platelets.
Main Results:
- Macrophages phagocytized AAPs via scavenger receptors, a process inhibited by fucoidan.
- AAPs enhanced LPS-induced secretion of TNF-α, IL-6, and IL-23 by macrophages.
- Apoptotic cells inhibited LPS-induced cytokine secretion.
- Dexamethasone pre-treatment of platelets reversed the enhancement of cytokine secretion.
Conclusions:
- Macrophage interaction with AAPs leads to scavenger receptor-mediated uptake and enhanced pro-inflammatory cytokine production.
- Activated platelets at inflammatory sites may worsen macrophage pro-inflammatory activation.
- Dexamethasone-loaded platelets show promise for treating unresolved inflammation.
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