Double-negative T cells ameliorate psoriasis by selectively inhibiting IL-17A-producing γδlow T cells.

BACKGROUND: Psoriasis is a chronic immune-mediated skin condition. Although biologic treatments are effective in controlling psoriasis, some patients do not respond or lose response to these therapies. Thus, new strategies for psoriasis treatment are still urgently needed. Double-negative T cells (DNT) play a significant immunoregulatory role in autoimmune diseases. In this study, we aimed to evaluate the protective effect of DNT in psoriasis and explore the underlying mechanism. METHODS: We conducted a single adoptive transfer of DNT into an imiquimod (IMQ)-induced psoriasis mouse model through tail vein injection. The skin inflammation and IL-17A producing γδ T cells were evaluated. RESULTS: DNT administration significantly reduced the inflammatory response in mouse skin, characterized by decreased skin folds, scales, and red patches. After DNT treatment, the secretion of IL-17A by RORc+ γδlow T cells in the skin was selectively suppressed, resulting in an amelioration of skin inflammation. Transcriptomic data suggested heightened expression of NKG2D ligands in γδlow T cells within the mouse model of psoriasis induced by IMQ. When blocking the NKG2D ligand and NKG2D (expressed by DNT) interaction, the cytotoxic efficacy of DNT against RORc+IL17A+ γδlow T cells was attenuated. Using Ccr5-/- DNT for treatment yielded evidence that DNT migrates into inflamed skin tissue and fails to protect IMQ-induced skin lesions. CONCLUSIONS: DNT could migrate to inflamed skin tissue through CCR5, selectively inhibit IL-17-producing γδlow T cells and finally ameliorate mouse psoriasis. Our study provides feasibility for using immune cell therapy for the prevention and treatment of psoriasis in the clinic.

Cobra venom P-III class metalloproteinase atrase A induces inflammatory response and cell apoptosis in endothelial cells via its metalloproteinase domain.

Snake venom metalloproteinases (SVMPs), which are a critical component of viperid and crotalid venoms, play various important roles in the pathogenesis of snakebite envenomation. The SVMPs from elapid venoms are not well elucidated, as compared with those from viperid and crotalid venoms. Atrase A is a nonhemorrhagic P-III SVMP purified from Naja atra venom that possesses only weak fibrinogenolytic activity. In our prior study, we found that atrase A detached adherent cells from the substrate. In this work, we investigated further the effect and mechanism of atrase A on endothelial cells. Oxidative damage, inflammatory mediators, apoptosis, and activation of the NF-κB and MAPK signaling pathways were measured after HMEC-1 cells were exposed to atrase A. The results showed that HMEC-1 cells released inflammatory mediators, exihibited oxidative damage and apoptosis after exposure to atrase A. The Western blot analysis results revealed that atrase A increased Bax/Bcl-2 and caspase-3 levels and activated the NF-κB and MAPK signaling pathways in endothelial cells. The effects on endothelial cells were nearly completely abolished after atrase A was treated with ethylenediamine tetraacetic acid. These results showed that atrase A led to an inflammatory response, cellular injury and apoptosis in endothelial cells, and this effect was due to its metalloproteinase domain. The study contributes to a better understanding of the structures and functions of cobra venom P-III class metalloproteinases.