Physiologic and pathophysiologic roles of interaction between C‐type lectin‐like receptor 2 and podoplanin: partners from in utero to adulthood

Abstract

Summary A platelet activation receptor, C‐type lectin‐like receptor 2 (CLEC‐2), has been identified as a receptor for a platelet‐activating snake venom, rhodocytin. CLEC‐2 protein is highly expressed in platelets/megakaryocytes, and at lower levels in liver Kupffer cells. Recently, podoplanin has been revealed as an endogenous ligand for CLEC‐2. Podoplanin is expressed in certain types of tumor cells, fibroblastic reticular cells (FRCs) in lymph nodes, kidney podocytes, and lymphatic endothelial cells, but not in vascular endothelial cells. CLEC‐2 in platelets cannot have access to podoplanin under normal conditions, but they interact with each other under pathologic conditions or during developmental stages, and play various pathophysiologic roles. CLEC‐2 facilitates hematogenous metastasis of podoplanin‐expressing tumors. During development, the interaction between CLEC‐2 and podoplanin in lymphatic endothelial cells or neuroepithelial cells facilitates blood–lymphatic vessel separation and cerebrovascular patterning and integrity, respectively. In adulthood, platelet CLEC‐2 binding to FRCs is crucial for maintenance of the integrity of high endothelial venules in lymph nodes. Podoplanin‐expressing FRC‐like cells have recently been identified in the bone marrow, and facilitate megakaryocyte proliferation and proplatelet formation by binding to megakaryocyte CLEC‐2. Podoplanin is inducibly expressed in liver monocytes and keratinocytes during Salmonella infection and wound healing, and regulates thrombus formation in the liver and controlled wound healing, respectively. By binding to unknown ligands, platelet CLEC‐2 regulates the maintenance of vascular integrity during inflammation, thrombus stability under flow, and maintenance of quiescence of hematopoietic stem cells. Podoplanin is expressed in various cells, and additional roles of the CLEC‐2–podoplanin interaction will be revealed in the future.

Characterization of Mice with a Platelet-Specific Deletion of the Adapter Molecule ADAP

“…The exact mechanism underlying the blood-lymphatic vessel separation is still controversially debated. Different hypotheses are discussed, including the "platelet plug theory," the "platelet granule content theory," and the "prevention of backflow at the lymphovenous junction theory" (38). Soluble mediators released from activated platelets, including TGF-␤1 in particular, inhibit the proliferation and migration of lymphatic endothelial cells (39).…”

HemITAM: A single tyrosine motif that packs a punch

“…A more recent report, however, attributed Clec-2 on mouse B cells to the acquisition from exogenous sources, for example, by trogocytosis, and showed that Clec-2 on mouse myeloid cells is lost during the entrance of these cells into secondary lymphoid organs (45). The function of CLEC-2 on platelets is well defined as stimulating platelet activation and aggregation (10,24,41). Chimeric receptors composed of the cytoplasmic tail of Clec-2 fused to the transmembrane and extracellular domains of Dectin-1-stimulated phagocytosis and the production of proinflammatory cytokines by mouse neutrophils, but not a respiratory burst (36).…”

“…Originally, CLEC-2 was found to act as a receptor of the snake venom rhodocytin (24), with the transmembranous glycoprotein podoplanin later identified as an endogenous cellular ligand of CLEC-2 (24,40). Podoplanin is expressed on multiple cell types such as lymphatic endothelial cells, type I alveolar cells, and keratinocytes but also on some tumor cells (41). In the original report on human CLEC-2 (38), the broad presence of transcripts encoding this protein was noted in bone marrow cells and among peripheral blood mononuclear cells, including myeloid cells such as monocytes, DCs, and granulocytes, and a few NK cell clones, indicating a heterogeneous expression pattern.…”

“…Rather, Clec-2 ligation on myeloid cells was shown to selectively potentiate TLR-mediated interleukin-10 (IL-10) production (44). The multiple biological functions of the interaction of CLEC-2 with its natural ligand podoplanin also include a role in bloodlymphatic vessel separation during development, the maintenance of vascular integrity under inflammatory conditions, and wound healing [reviewed in (41)]. …”

Illustrated State‐of‐the‐Art Capsules of the ISTH 2019 Congress in Melbourne, Australia

“…We have shown that platelets facilitate lung development through the interaction between the platelet activation receptor C-type lectin-like receptor-2 (CLEC-2), and its ligand membrane protein, podoplanin. [115][116][117] CLEC-2 deletion in mouse platelets led to neonatal lethality due to lung malformation and respiratory failure. In the primary alveolar septa of these embryos, α-smooth muscle actin-positive alveolar duct myofibroblasts (adMYFs) were almost absent, which was caused by abnormal differentiation of lung mesothelial cells (luMCs) into adMYFs.…”