CD137 on inflamed lymphatic endothelial cells enhances CCL21‐guided migration of dendritic cells

Abstract

CD137/TNFR9/41BB was originally described as a surface molecule present on activated T and NK cells. However, its expression is broader among leukocytes, and it is also detected on hypoxic endothelial cells and inflamed blood vessels, as well as in atherosclerotic lesions. Here, we demonstrate that lymphatic endothelial cells (LECs) up-regulate CD137 expression from undetectable baseline levels on stimulation with TNF-α, LPS, and IL-1β. CD137 cross-linking with an agonistic mAb results in NF-κB nuclear translocation, followed by up-regulation of VCAM and a 3-fold increase in the production of the chemokine CCL21. Accordingly, there is a 50% increase in CCR7-dependent migration toward conditioned medium from activated LECs on CD137 cross-linking with the agonistic mAb or the natural ligand (CD137L). Such an enhancement of cell migration is also observed with monocyte-derived dendritic cells transmigrating across CD137-activated LEC monolayers. Using explanted human dermal tissue, we found that inflamed skin contains abundant CD137(+) lymphatic vessels and that ex vivo incubation of explanted human dermis with TNF-α induces CD137 expression in lymphatic capillaries. More interestingly, treatment with CD137 agonistic antibody induces CCL21 expression and DC accumulation close to lymphatic vessels. Collectively, our results demonstrate that the inflammatory function of lymphatic vessels can be regulated by CD137.

Notch signalling restricts inflammation and serpine1 expression in the dynamic endocardium of the regenerating zebrafish heart

“…Notch inhibition (Fig. 5B) also led to increased expression of inflammatory markers and regulators ( ptgs2b, pde7a, sgpl1) (Smith et al, 2003;Ogryzko et al, 2014) and the pro-inflammatory endothelial genes arg2 (Ryoo et al, 2008) and tnfrsf9a (CD137) (Olofsson et al, 2008;Teijeira et al, 2012) (Fig. 5B).…”

“…Also, Notch signalling abrogation resulted in increased wound-related endothelial and inflammatory gene expression and an increased abundance of macrophages. This anti-inflammatory role of Notch might be direct, by regulating endothelial inflammatory genes such as tnfrsf9a (Olofsson et al, 2008;Teijeira et al, 2012), or might be linked to the appearance and maturation of the endocardium upon Notch inhibition. Cardiac injury induces the dedifferentiation and proliferation of existing cardiomyocytes, which peaks at 7 dpci (Kikuchi et al, 2010;Sallin et al, 2014;Bednarek et al, 2015), and endocardial signals are implicated in this process Zhao et al, 2014).…”

Mitochondrial Morphological and Functional Reprogramming Following CD137 (4-1BB) Costimulation

“…T lymphocytes were costimulated with recombinant with plate-bound anti-CD3ε (0.5 μg/mL, clone OKT3) and anti-CD137 (10 μg/ml, clone 6B4 or urelumab) or the respective isotype control antibodies at 2. cells/mL for 72 h in complete media. In some experiments plate bound anti CD3 (0.5 μg/mL) and 4-1BBL or GAG protein coated beads (ratio 1.2) were used (27). In some experiments, CD8 + + T cells were additionally costimulated with plate-bound anti-CD28 (10 μg/mL, 37.51) in the presence or absence of anti-CD137.…”

Lymphangiogenesis and Inflammation—Looking for the “Missing Pieces” of the Puzzle

“…Also, lymphatic endothelial cell proliferation during acute inflammation is governed not only by VEGF-C and VEGF-D action through VEGFR-3 but also by other factors as FGF-2, PLGF-2, HGF, EGF, and KC/CXCL17 (Lachance et al 2013). Recently, Teijeira et al (2012) demonstrated that CD137 marker, originally described as a surface molecule present in activated T and NK cells, was upregulated in lymphatic endothelial cells on stimulation with TNF-a, lipopolysaccharide, and IL-1b. Tissue inflammation modulates gene expression of lymphatic endothelial cells and dendritic cell migration in a stimulus-dependent manner by Prox-1, VEGFR-3, and LYVE-1 significant downregulation following contact hypersensitivity (Vigl et al 2011).…”