Opposing roles of endothelial and leukocyte-expressed IL-7Rα in the regulation of psoriasis-like skin inflammation

Abstract

The interleukin 7 receptor alpha chain (IL-7Rα) is predominately expressed by lymphocytes, and activation by its ligand IL-7 supports the development and maintenance of T cells and boosts T-cell mediated immunity. We recently reported that lymphatic endothelial cells (LECs) in dermal lymphatics also express IL-7 and its receptor chains (IL-7Rα and CD132) and that IL-7 supports lymphatic drainage. This suggested that activation of IL-7Rα signaling in lymphatics could exert inflammation-resolving activity, by promoting the clearance of excess tissue fluid. Here we investigated how the potentially opposing effects of IL-7Rα signaling in immune cells and in the lymphatic vasculature would affect the development and progression of psoriasis-like skin inflammation. We found that during acute and chronic skin inflammation mice with an endothelial-specific deletion of IL-7Rα (IL-7Rα ΔEC mice) developed more edema compared to control mice, as a consequence of impaired lymphatic drainage. However, systemic treatment of wild-type mice with IL-7 exacerbated edema and immune cell infiltration in spite of increasing lymphatic drainage, whereas treatment with IL-7Rα blocking antibody ameliorated inflammatory symptoms. These data identify IL-7Rα signaling as a new pathway in psoriasis-like skin inflammation and show that its pro-inflammatory effects on the immune compartment override its anti-inflammatory, drainage-enhancing effects on the endothelium.

Mechanosensitive ACKR4 scavenges CCR7 chemokines to facilitate T cell de-adhesion and passive transport by flow in inflamed afferent lymphatics

“…Experiments were either performed in 8-9 week old female mice (steady-state data) or in 11 -13 week old male mice (TPA inflammation data). Lymphatic drainage in the ear was measured as described previously (Karaman et al, 2015;Proulx et al, 2013;Vranova et al, 2019). In brief, 3mL P20D800 (3mM synthesized as previously described (Vranova et al, 2019)) were injected intradermally into shaved ears of anesthetized mice (2.5% isoflurane inhalation anesthesia).…”

“…Lymphatic drainage in the ear was measured as described previously (Karaman et al, 2015;Proulx et al, 2013;Vranova et al, 2019). In brief, 3mL P20D800 (3mM synthesized as previously described (Vranova et al, 2019)) were injected intradermally into shaved ears of anesthetized mice (2.5% isoflurane inhalation anesthesia). Fluorescence was measured in vivo right after injection as well as 1, 2, 4, 6 and 24 h later with an IVIS imaging system (PerkinElmer).…”

Association of Behçet disease with psoriasis and psoriatic arthritis

“…On the surface, BD and PSO render drastically different pictures. The former most often presents with painless oral or genital ulcers accompanied by nonspecific cutaneous lesions, such as those of erythema nodosum 15 (EM), while with the latter is accentuated by erythematous and nonpruritic scaly plaques on exposed skin surfaces 16 , 17 . Aside from the conspicuous clinical features, however, these two share key common ingredients that play a major role in the immuno-pathophysiology, namely deranged Th1/Th17 regulation 18 , and the involvement of autoinflammation 19 – 21 .…”

Anti-Inflammatory Activity of a Medicinal Herb Extract Mixture, HM-V, on an Animal Model of DNCB-Induced Chronic Skin Inflammation

“…Chronic skin inflammation refers to a general skin barrier disorder characterized by skin lesions (such as dry skin, itching, eczema, and erythema) and an immune hypersensitivity reaction caused by the infiltration of immune cells (such as lymphocytes, eosinophils, and mast cells) [ 21 , 22 , 23 ]. Previously reports, various types of chronic dermatitis, including atopic dermatitis, were shown predominantly caused by activation of Th2 cells.…”