Abstract
C-type lectin-like receptor 2 (CLEC-2) is considered as a potential drug target in settings of wound healing, inflammation, and infection. A potential barrier to this is evidence that CLEC-2 and its ligand podoplanin play a critical role in preventing lymphatic vessel blood filling in mice throughout life. In this study, this aspect of CLEC-2/podoplanin function is investigated in more detail using new and established mouse models of CLEC-2 and podoplanin deficiency, and models of acute and chronic vascular remodeling. We report that CLEC-2 expression on platelets is not required to maintain a barrier between the blood and lymphatic systems in unchallenged mice, post-development. However, under certain conditions of chronic vascular remodeling, such as during tumorigenesis, deficiency in CLEC-2 can lead to lymphatic vessel blood filling. These data provide a new understanding of the function of CLEC-2 in adult mice and confirm the essential nature of CLEC-2-driven platelet activation in vascular developmental programs. This work expands our understanding of how lymphatic blood filling is prevented by CLEC-2-dependent platelet function and provides a context for the development of safe targeting strategies for CLEC-2 and podoplanin.
Highlights
C-type lectin-like receptor 2 (CLEC-2) is a hemITAM containing receptor that is highly expressed on platelets and regulates many of the non-classical functions of these cells, including in inflammation and infection [1]
We show that the interaction between platelet expressed CLEC-2 and podoplanin is not required to protect the lymphatic system from blood filling in unchallenged mice once development is complete
Western blotting and ELISA detected soluble podoplanin in the plasma of all Pdpn K164STOP animals tested but not all wildtype animals indicating that the primary cause for the loss of podoplanin expression is shedding of the protein from the cell surface (Figure 1ei–ii)
Summary
C-type lectin-like receptor 2 (CLEC-2) is a hemITAM containing receptor (defined by a single YxxL sequence) that is highly expressed on platelets and regulates many of the non-classical functions of these cells, including in inflammation and infection [1]. Genetic studies in mice have shown that activation of platelets via the interaction of podoplanin and CLEC-2 is essential during development to prevent deleterious blood filling of the lymphatic system [18,19,20,21]. This maintenance in separation between the two developing vasculatures is understood to occur by at least two distinct mechanisms, dependent on anatomical location. CLEC-2-mediated activation of Platelets, Early Online: 1–16 platelets by lymphatic endothelial cells and podoplanin-expressing stromal cells is thought to reduce the severity of blood leakage from the developing veins and may contribute to the organization of lymphatic endothelial cell clusters, preventing the developing lymphatics from becoming overwhelmed and bloodfilled and malformed [23]
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