Inorganic arsenic, a well-known human carcinogen, poses a major threat to global health. Given the immunosuppressive potentials of inorganic arsenic as well as limited understanding of this metalloid on antigen-presenting dendritic cells (DCs), we systematically screened the immune targets in response to arsenic treatment, as well as its possible molecular mechanism in cultured murine DCs. Our results denoted that arsenite (As) significantly induced immune tolerance by down-regulating the expression of phenotypic molecules, pro-inflammatory factors and T-lymphocyte helper (Th)1/Th17-inducible cytokines in lipopolysaccharides (LPS)-stimulated myeloid-derived dendritic cells (BMDCs). Inconsistent with dampened phosphorylation of immune-related proteins (nuclear factor kappa-B) NF-κB, p38 and JNK, the metalloid drastically induced the expression of Heme oxygenase-1 (HO-1) protein, which enlightened us to continuously explore the possible roles of HO-1 pathway in As-induced immune tolerance in BMDCs. In this respect, immunosuppressive properties of HO-1 pathway in BMDCs were firstly confirmed through pharmacological overexpression of HO-1 by both CoPP and CORM-2. By contrast, limited HO-1 expression by HO-1 inhibitor ZnPP specifically alleviated As-mediated down-regulation of CD80, chemokine factor C-C chemokine receptor 7 (CCR7), tumor necrosis factor (TNF) -α, Interleukin (IL)-23 and IL-6, which reminds us the peculiarity of HO-1 in As-induced immune tolerance in murine DCs. Based on these experimental findings, we postulated the immunosuppressive property of inorganic arsenic might be mediated partially by HO-1 in DCs, thus contributing to the interactions of DCs-polarized differentiation of T-lymphocyte subtype as well as the development of infections and malignant diseases.
Authors: Jinlong Li, Yuanyuan Guo, Xiaoxu Duan, Bing Li
; Full Source: Chemosphere 2020 Sep 30;264(Pt 2):128452. doi: 10.1016/j.chemosphere.2020.128452.