Journal
CELL DEATH AND DIFFERENTIATION
Volume 28, Issue 11, Pages 3009-3021Publisher
SPRINGERNATURE
DOI: 10.1038/s41418-021-00797-w
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Funding
- Jiangsu Provincial Key Medical Center [YXZXA2016002]
- Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD)
- Key Cultivation of Wannan Medical College Foundation, Anhui, China [WK2016ZF08]
- Anhui Provincial Key Research and Development Project, China [201904a07020036]
- Oklahoma Medical Research Foundation
- NIH [HL131474, AI151371, DK048247]
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The study found that CLEC4F is a key receptor on Kupffer cells in the liver that mediates the phagocytosis of desialylated platelets. This discovery provides new insights into the pathogenesis of thrombocytopenia in disease conditions like sepsis.
The liver has recently been identified as a major organ for destruction of desialylated platelets. However, the underlying mechanism remains unclear. Kupffer cells, which are professional phagocytic cells in the liver, comprise the largest population of resident tissue macrophages in the body. Kupffer cells express a C-type lectin receptor, CLEC4F, that recognizes desialylated glycans with an unclear in vivo role in mediating platelet destruction. In this study, we generated a CLEC4F-deficient mouse model (Clec4f(-/-)) and found that CLEC4F was specifically expressed by Kupffer cells. Using the Clec4f(-/-) mice and a newly generated platelet-specific reporter mouse line, we revealed a critical role for CLEC4F on Kupffer cells in mediating destruction of desialylated platelets in the liver in vivo. Platelet clearance experiments and ultrastructural analysis revealed that desialylated platelets were phagocytized predominantly by Kupffer cells in a CLEC4F-dependent manner in mice. Collectively, these findings identify CLEC4F as a Kupffer cell receptor important for the destruction of desialylated platelets induced by bacteria-derived neuraminidases, which provide new insights into the pathogenesis of thrombocytopenia in disease conditions such as sepsis.
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