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Abstract: Objective To investigate the regulatory role of vitamin D3 ( VD3 ) -mediatedtumor necrosis factor-alpha induced protein 8-like protein 2 ( TIPE2) on macrophage function andphenotype in chronic rhinosinusitis with nasal polyps (CRSwNP). Methods Peripheral blood samples were collected from patients with CRSwNP as the CRSwNP group, and from patients under went surgery for isolated nasal septal deviation as the Control group. RT-qPCR and Western blotting were used to detect the expression levels of TIPE2 and Arginase-1 ( Arg-1) in peripheral blood, andchemiluminescence was used to detect the changes in VD3 concentration in peripheralblood. J774A. 1 macrophages were cultured in vitro and divided into 5 groups: silenced TIPE2 (siTIPE2#2) group and its negative control ( si-NC) group, negative control for TIPE2 overexpression (oe-NC) group, oe-NC combined with VD3 treatment group ( oe-NC + VD3 group), and overexpressed TIPE2 recombinant vector ( oe-TIPE2 ) combined with VD3 treatment group ( oeTIPE2 + VD3 group). In addition, a mouse model of CRSwNP was established, with CRSwNP mice divided into 3 groups: empty vector treatment group (CRSwNP + empty vector group), CRSwNP + oeTIPE2 group, and CRSwNP + oe-TIPE2 + VD3 group. Peripheral blood and macrophages were collected fr om each group of mice. RT-qPCR and Western blotting were used to detect the expression levels of TIPE2 and Arg-1 in macrophages. Enzyme-linked immunosorbent assay (ELISA) was used to detect the levels of interleukin ( IL ) -4 and IL-13 in cell culture supernatants and mouse sera in eachgroup. Results Compared to those in the control group, VD3 concentration was decreased in the CRSwNP group, while the expression levels of TIPE2 and Arg-1, as well as the serum concentrations of IL-4and IL-13, were upregulated (all P< 0. 05). There was a significant positive correlation between Arg-1 and TIPE2 levels (r =0. 994, P<0. 01), and both Arg-1 and TIPE2 levels were significantly negatively correlated with VD3 concentration (r = -0. 652, P<0. 01; r = -0. 745, P<0. 01). Compared to thosein the si-NC group, the expression levels of Arg-1 and IL-4 and IL-13 concentrations decreased in the siTIPE2#2 group (all P< 0. 05). Compared to those in the oe-NC group, the expression levels of TIPE2 and Arg-1, as well as IL-4 and IL-13 concentrations, decreased in the oe-NC + VD3 group (all P <0. 05). Moreover, compared to those in the oe-NC + VD3 group, the expression levels of TIPE2 and Arg-1, as well as IL-4 and IL-13 concentrations, increased in the oe-TIPE2 + VD3 group (all P < 0. 05).Compared to those in the CRSwNP + emptyvector group, the expression levels of TIPE2 and Arg-1 increased in the CRSwNP + oe-TIPE2 group, while VD3 concentration decreased and the serum concentrations of IL-4 and IL-13 increased (all P<0. 05). Compared to those in the CRSwNP + oe-TIPE2 group,the expression levels of TIPE2 and Arg-1 decreased in the CRSwNP + oe-TIPE2 + VD3 group, while theVD3 concentration increased and the serum concentrations of IL-4 and IL-13 decreased (all P<0. 05).Conclusion VD3 inhibits the expression of Arg-1, IL-4, and IL-13 in CRSwNP by downregulatingTIPE2 expression.

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