DPP-4 inhibitor linagliptin ameliorates imiquimod-induced psoriasis-like skin alterations in type 2 diabetic mice by inhibiting the MAPK/NF-κB inflammatory pathway

Abstract

Studies have shown that the DPP-4 inhibitor was effective in improving skin damage in patients with psoriasis, but the exact mechanism was not known. To investigate the therapeutic effects of linagliptin in mice with type 2 diabetes mellitus (T2DM) with psoriasis and its possible therapeutic mechanisms. A total of 32 db/db mice and 16 db/m mice were randomly divided into six groups: normal group, psoriasis group, diabetes group, diabetes combined with psoriasis group, linagliptin-treated diabetes group, and linagliptin-treated diabetes combined with psoriasis group. The levels of serum fasting blood glucose, total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol were measured; the levels of serum FINS were determined by enzyme-linked immunoassay and the insulin resistance index was calculated. Basic parameters of diabetes, Psoriasis Area and Severity Index, histopathology of skin, the expression of interleukin (IL)-17A, IL-23, IL-22, and tumor necrosis factor (TNF)-α, and expression levels of measuring p-ERK, p-MAPK and p-nuclear factor kappa B (NF-κB) in skin tissues were measured. After treatment with linagliptin, insulin resistance, and TC and TG levels were reduced in mice with T2DM and psoriasis (p < .05). Moreover, the degree of epidermal tissue thickening, number of keratinized layers, and inflammatory cell infiltration were also reduced (p < .05), as well as the expression levels of inflammatory factors: TNF-α, IL-1β, IL-17A, IL-23, and p-P38/P38, p-ERK/ERK, p-P65/P65 proteins (p < .05). Linagliptin significantly reduced the extent of skin lesions and skin inflammation. The underlying mechanism of this compound may be related to the inhibition of MAPK/NF-κB inflammatory pathways and the consequential improvement of insulin resistance.Significance Statement: In this study, we evaluated the therapeutic effect of the DPP-4 inhibitor linagliptin using a murine model of type 2 diabetes combined with psoriasis, and its potential mechanisms of action were further explored. The results of this study will help to uncover the pathogenesis of type 2 diabetes and psoriasis and, more importantly, provide a theoretical basis for the search for safe and effective drugs in the treatment of this specific patient population.

Keywords: DPP-4 inhibitor; Linagliptin; Psoriasis; inflammation; type 2 diabetes mellitus.