Department of Dermatology, The First Hospital of China Medical University, Shenyang, China.
Key Laboratory of Immunodermatology, Ministry of Health and Ministry of Education, Shenyang, China.
Exp Dermatol. 2022 Sep;31(9):1330-1340. doi: 10.1111/exd.14580. Epub 2022 May 3.
Macrophages, which serve as a bridge between innate and adaptive immunity, play an important role in sporotrichosis. Sporothrix schenckii infections can produce immune responses such as macrophage polarization and inflammatory factor secretion. In the early stages of inflammation, the expression of DAB2 in macrophages is increased, which controls the secretion of inflammatory factors and affects the polarization of macrophages. However, the expressions and mechanisms of DAB2 in sporotrichosis are not clear. In this study, we examined the expression of DAB2 and its regulation of inflammatory factors under conditions of Sporothrix schenckii infection. Our results indicated that the Sporothrix schenckii infection increased the expression of DAB2 and revealed a mixed M1/M2-like type of gene expression in BMDMs with the inhibited Il-6, Il1-β and Arg-1 and induced Tnf-α, Il-10 and Mgl-1. The deficiency of Dab2 gene suspended the changes of cytokines. In addition, JNK activity in BMDMs was inhibited by Sporothrix schenckii infection, leading to an increase in c-JUN. We also identified c-JUN as a transcription factor for Dab2 through chromatin immunoprecipitation and luciferase reporter assays. In an in vivo mouse model, sporotrichosis-induced skin lesions were accompanied with an upregulation of c-JUN and inhibition of JNK activity, which were in accord with findings from in vitro experiments. Taken together, these findings indicate that in the early stages of Sporothrix schenckii infection there is a promotion of DAB2 expression through the JNK/c-JUN pathway, effects that can then control the expression of inflammatory factors.
巨噬细胞作为先天免疫和适应性免疫之间的桥梁，在孢子丝菌病中发挥着重要作用。申克孢子丝菌感染可产生免疫反应，如巨噬细胞极化和炎症因子分泌。在炎症的早期阶段，巨噬细胞中 DAB2 的表达增加，控制炎症因子的分泌，影响巨噬细胞的极化。然而，DAB2 在孢子丝菌病中的表达和机制尚不清楚。在这项研究中，我们研究了 DAB2 的表达及其在申克孢子丝菌感染条件下对炎症因子的调节作用。结果表明，申克孢子丝菌感染增加了 DAB2 的表达，并在 BMDMs 中呈现出一种混合的 M1/M2 样基因表达类型，同时抑制了 Il-6、Il1-β 和 Arg-1，诱导了 Tnf-α、Il-10 和 Mgl-1。Dab2 基因缺失抑制了细胞因子的变化。此外，申克孢子丝菌感染抑制了 BMDMs 中的 JNK 活性，导致 c-JUN 增加。我们还通过染色质免疫沉淀和荧光素酶报告基因实验鉴定了 c-JUN 是 Dab2 的转录因子。在体内小鼠模型中，孢子丝菌病诱导的皮肤损伤伴随着 c-JUN 的上调和 JNK 活性的抑制，与体外实验结果一致。综上所述，这些发现表明，在申克孢子丝菌感染的早期阶段，通过 JNK/c-JUN 途径促进了 DAB2 的表达，从而控制了炎症因子的表达。
