Instantaneous depolarization of T cells via dopamine receptors, and inhibition of activated T cells of Psoriasis patients and inflamed human skin, by D1‐like receptor agonist: Fenoldopam

Summary Activated T cells are pathological in various autoimmune and inflammatory diseases including Psoriasis, and also in graft rejection and graft‐versus‐host‐disease. In these pathological conditions, selective silencing of activated T cells through physiological receptors they express remains a clinical challenge. In our previous studies we found that activation of dopamine receptors (DRs) in resting human T cells activates these cells, and induces by itself many beneficial T cell functions. In this study, we found that normal human T cells express all types of DR s, and that expression of D1R, D4R and D5R increases profoundly after T cell receptor (TCR) activation. Interestingly, DR agonists shift the membrane potential ( V m ) of both resting and activated human T cells, and induces instantaneous T cell depolarization within 15 seconds only. Thus, activation of DRs in T cells depolarize these immune cells, alike activation of DRs in neural cells. The skin of Psoriasis patients contains 20‐fold more D1R + T cells than healthy human skin. In line with that, 25‐fold more D1R + T cells are present in Psoriasis humanized mouse model. Highly selective D1‐like receptor agonists, primarily Fenoldopam (Corlopam) – a D1‐like receptor agonist and a drug used in hypertension, induced the following suppressive effects on activated T cells of Psoriasis patients: reduced chemotactic migration towards the chemokine SDF ‐1/ CXCL 12; reduced dramatically the secretion of eight cytokines: tumor necrosis factor‐ α , interferon‐ γ , interleukin‐1 β ( IL ‐1 β ), IL ‐2, IL ‐4, IL ‐6, IL ‐8 and IL ‐10; and reduced three T cell activation proteins/markers: CD 69, CD 28 and IL ‐2. Next, we invented a novel topical/dermal Fenoldopam formulation, allowing it to be spread on, and providing prolonged and regulated release in, diseased skin. Our novel topical/dermal Fenoldopam: reduced secretion of the eight cytokines by activated human T cells; reduced IL ‐1 β and IL ‐6 secretion by human lipopolysaccharide‐inflamed skin; eliminated preferentially >90% of live and large/proliferating human T cells. Together, our findings show for the first time that both resting and activated T cells are depolarized instantaneously via DR s, and that targeting D1‐like receptors in activated T cells and inflamed human skin by Fenoldopam, in Psoriasis, and potentially in other T cell‐mediated diseases, could be therapeutic. Validation in vivo is required.