Endometriosis is an estrogen-dependent chronic inflammatory disease and is associated etiologically with environmental endocrine disruptor (EED) exposure. 4-nonylphenol (NP), a widely found EED, has weak estrogenic activity and modulates plasmacytoid dendritic cell (pDC) function in vitro and in vivo. We aimed to elucidate the immunomodulatory effect of NP on the development of endometriosis, particularly focusing on pDCs. This study established a surgically induced endometriosis murine model (C57BL/6) under conditions of NP treatment that are relevant to the level and route of human exposure. Multi-parametric flow cytometry was used for analysis of infiltrated immune cell subsets in lesions. The results showed that NP exposure significantly promoted endometriotic lesion growth, survival and angiogenesis development of lesions as well as pDC accumulation in the lesions in mice. Adoptive transfer of NP-conditioned pDCs into mice significantly enhanced lesion development and local pDC infiltration, whereas NP-conditioned conventional dendritic cells did not affect lesion growth. In vitro functional analysis showed that NP-conditioned pDCs in lesions expressed high levels of CD36, a scavenger receptor and NP-conditioned splenic pDCs secreted an enhanced level of IL-10 in response to apoptotic cell recognition in a CD36-dependent manner. Furthermore, we observed that local treatment with blocking antibodies against IL-10 and CD36 on the day of surgery significantly inhibited lesion development. NP exposure also altered the estrous cycle in mice. The results suggest that chronic and low-dose exposure to NP enhances endometriotic lesion growth by altering pDC homeostasis and function. This study has important implications for understanding the environment-innate immunity interaction in human endometriosis.

中文翻译：

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一种突出的环境内分泌干扰物 4-壬基酚通过浆细胞样树突细胞促进子宫内膜异位症的发展。

子宫内膜异位症是一种雌激素依赖性慢性炎症性疾病，在病因上与环境内分泌干扰物 (EED) 暴露有关。4-壬基苯酚 (NP) 是一种广泛发现的 EED，具有弱雌激素活性并在体外和体内调节浆细胞样树突细胞 (pDC) 功能. 我们旨在阐明 NP 对子宫内膜异位症发展的免疫调节作用，特别是对 pDCs。本研究在与人类暴露水平和途径相关的 NP 治疗条件下建立了手术诱导的子宫内膜异位症小鼠模型 (C57BL/6)。多参数流式细胞术用于分析病变中浸润的免疫细胞亚群。结果表明，NP暴露显着促进了小鼠子宫内膜异位病变的生长、存活和病变的血管生成发展以及pDC在病变中的积累。将 NP 条件下的 pDC 过继转移到小鼠体内显着增强了病变发展和局部 pDC 浸润，而 NP 条件下的常规树突细胞不影响病变生长。体外功能分析表明，病变中 NP 条件下的 pDCs 表达高水平的 CD36，一种清道夫受体，并且 NP 条件下的脾脏 pDCs 以 CD36 依赖性方式响应凋亡细胞识别而分泌增加水平的 IL-10。此外，我们观察到在手术当天用针对 IL-10 和 CD36 的封闭抗体进行局部治疗显着抑制了病变的发展。NP 暴露也改变了小鼠的发情周期。结果表明，长期和低剂量暴露于 NP 会通过改变 pDC 稳态和功能来增强子宫内膜异位病变的生长。这项研究对于理解人类子宫内膜异位症的环境-先天免疫相互作用具有重要意义。