The CLEC-2–podoplanin axis controls the contractility of fibroblastic reticular cells and lymph node microarchitecture

Abstract

In lymph nodes, fibroblastic reticular cells (FRCs) form a collagen-based reticular network that supports migratory dendritic cells (DCs) and T cells and transports lymph. A hallmark of FRCs is their propensity to contract collagen, yet this function is poorly understood. Here, we demonstrate that podoplanin (PDPN) regulated actomyosin contractility in FRCs. Under resting conditions, when FRCs are unlikely to encounter mature DCs expressing the PDPN receptor, CLEC-2, PDPN endowed FRCs with contractile function and exerted tension within the reticulum. Upon inflammation, CLEC-2 on mature DCs potently attenuated PDPN-mediated contractility, resulting in FRC relaxation and reduced tissue stiffness. Disrupting PDPN function altered the homeostasis and spacing of FRCs and T cells, resulting in an expanded reticular network and enhanced immunity.

Altered Dermal Fibroblasts in Systemic Sclerosis Display Podoplanin and CD90

“…43 More important, in the lymph node environment, Pdpn promotes actinomyosin contractility in fibroblastic reticular cells via the RhoA/C-ROCK signaling pathway. 13,77 Shifts in fibroblast contractility dependent on Pdpn binding status may be especially relevant in the fibrotic setting given the attention being given to the role of matrix stiffness and mechanotransduction in fibroblasts. 78 CD90 has been linked to efficient wound closure.…”

Podoplanin promotes malignancy through a diversity of strategies

“…In fact, the only function assigned to PDPN in normal adult tissues is related to lymphoid organs and the immune response [3][4][5] . PDPN null mice die immediately after birth due to respiratory problems.…”

CLEC-2 and podoplanin, partners again

“…In its severe form, VOD/SOS can be life-threatening and is associated with multiorgan failure (MOF); historical literature reports a mortality rate .80% on day 1100 for patients with severe VOD. 3 Although VOD/SOS pathophysiology is not completely understood, endothelial cell damage triggered by cytotoxic chemotherapy and a prothrombotic-hypofibrinolytic state are key features in the pathway. Historically, management of VOD/SOS involved primarily supportive care (diuretics, dialysis, and oxygen) and use of anticoagulants or antifibrinolytics, with limited efficacy and significant adverse effects, such as fatal bleeding with heparin or tissue plasminogen activator.…”

“…n Long-awaited news for hepatic veno-occlusive disease --------------------------------------------------------------------------------------------------- H epatic VOD, also called sinusoidal obstruction syndrome (SOS), is an early complication in patients undergoing HCT, with an estimated incidence of 13.7% (range, 0% to 62.3%), depending on criteria used to make the diagnosis (Seattle vs Baltimore criteria). 3 Clinically, VOD/SOS is characterized by jaundice, painful hepatomegaly, weight gain or fluid retention, and ascites. In its severe form, VOD/SOS can be life-threatening and is associated with multiorgan failure (MOF); historical literature reports a mortality rate .80% on day 1100 for patients with severe VOD.…”

“…On dendritic cells, CLEC-2 functions dually: it facilitates the migration of activated dendritic cells to, and also attenuates the contractility of fibroblastic reticular cells in, the draining lymph nodes. 3 On platelets, CLEC-2 was first identified as a receptor for a snake venom toxin, rhodocytin, that elicits aggregation of platelets through activation of Src and Syk nonreceptor tyrosine kinases. 2 However, the physiologic function and physiologically relevant ligand of platelet CLEC-2 remained elusive until it was found to be the receptor for the O-glycosylated protein podoplanin, 2 which is also known as Aggrus, T1a, and gp38, depending on the cell type in which the molecule was first found.…”