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• miR-181d-5p expression was downregulated in PBMCs of LN patients and MRL/lpr mice. • miR-181d-5p can directly target binding to MAPK8. • Overexpression of miR-181d-5p inhibited the phosphorylation of p38 and p44/42 in the THP-1 cells. • Overexpression of miR-181d-5p elevated THP-1 cell viability and decreased the inflammatory response. • Overexpression of miR-181d-5p decreased antinuclear antibodies and fibrosis levels in MRL/lpr mice. Lupus nephritis (LN) is a common immune disease. The microRNA (miR)-181d-5p is a potential target for treating kidney injury. However, the therapeutic role of miR-181d-5p in LN has not been investigated. This study aimed to investigate the role of miR-181d-5p in targeting mitogen-activated protein kinase 8 (MAPK8) and stimulating the MAPK signaling pathway in LN. RT-qPCR was performed to identify the variations in miR-181d-5p expression in peripheral blood mononuclear cells (PBMCs) obtained from 42 LN patients, 30 healthy individuals, 6 MRL/lpr mice and 6 C57BL/6 mice. Western blot was used to detect the effect of miR-181d-5p on the MAPK signaling pathway in THP-1 cells and MRL/lpr mice. Enzyme-linked immunosorbent assay (ELISA) was utilized to detect the effect of miR-181d-5p on antinuclear antibodies and inflammatory factors. A dual-luciferase reporter assay was used to verify whether miR-181d-5p directly targets MAPK8. Flow cytometry was performed to evaluate apoptosis rates in transfected THP-1 cells. miR-181d-5p expression was downregulated in PBMCs of LN patients (P < 0.01) and MRL/lpr mice (P < 0.05). A dual luciferase reporter assay demonstrated that miR-181d-5p inhibits MAPK8 (P < 0.01). Overexpression of miR-181d-5p inhibited the phosphorylation of p38 (P < 0.001) and p44/42 (P < 0.01). Moreover, miR-181d-5p decreased the apoptosis rate of THP-1 cells (P < 0.001), and reduced the secretion of IL-6 (P < 0.01) and TNF-α (P < 0.01). Furthermore, overexpression of miR-181d-5p decreased anti-dsDNA antibody (P < 0.05), anti-Sm antibody (P < 0.01), and fibrosis levels in MRL/lpr mice. Upregulation of miR-181d-5p showed anti-inflammatory and anti-apoptotic effects on THP-1 cells in vitro and kidney injury in vivo. These effects were achieved by miR-181d-5p targeting MAPK8 to inhibit phosphorylation of p38 and p44/42. These results may offer new insights for improving therapeutic strategies against lupus nephritis. [ABSTRACT FROM AUTHOR]

[Display omitted] • ∼85 nm spaced nanorods array timely switches macrophages from M1 to M2 phenotype. • Interrod spacing switches MΦs to M2 phenotype via the FN-integrin β1 -Akt1 pathway. • M2 cytokines enhanced by arrays facilitate osteogenesis via BMP2-TGF-SMAD pathway. Osseointegration is initiated by immune cell-derived inflammatory responses to the surfaces of implanted materials. However, the bio-molecular mechanisms by which nanotopographic features of implant surfaces immunomodulate osseointegration remain to be clarified. To this end, herein, three kinds of TiO 2 nanorod-like arrays on Ti with the interrod spacing of ∼0, 45 and 85 nm, termed as S0, S45 and S85, respectively, were hydrothermally grown, and their actions on the polarization of macrophages (MΦs) and MΦs-mediated contact osteogenesis of bone marrow-derived mesenchymal stromal cells (BMSCs) were explored, especially the involved signaling pathways. Compared to pure Ti (namely P-Ti), the nanorods-arrayed Ti activated FG-integrin α M β 2 -IKK-NF-κB signaling pathway in the adhered MΦs at initial 6 h while FN-integrin α 5 β 1 -PI3K-Akt1 pathway since 24 h, accelerating the transition of MΦs from pro-inflammatory (M1) to anti-inflammatory (M2) phenotype. With the cytokines secreted by M2 cells, the coatings activated the BMP2-TGFβ1-SMAD signaling pathway to enhance osteogenic differentiation of the recruited BMSCs in vitro. Also, the nanorods-coated Ti induced a proper immune microenvironment and accelerated bone apposition in rabbit tibia marrow cavities in vivo. Furthermore, owing to the favorable capacity of osteoimmunomodulation, the ∼85 nm spaced nanorods-arrayed coating exhibited satisfactorily in orchestrating osteogenic differentiation in vitro and in vivo. This work provides insights into nanotopographic features of implant surfaces immunomodulating contact osteogenesis. [ABSTRACT FROM AUTHOR]