KLF10 Mediated Epigenetic Dysregulation of Epithelial CD40/CD154 Promotes Endometriosis.
KLF10 Mediated Epigenetic Dysregulation of Epithelial CD40/CD154 Promotes Endometriosis.
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DOI：
10.1095/biolreprod.116.140764
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发表时间：
2016-09
影响因子：
3.6
通讯作者：
Daftary GS
中科院分区：
文献类型：
--
作者：
Delaney AA;Khan Z;Zheng Y;Correa LF;Zanfagnin V;Shenoy CC;Schoolmeester JK;Saadalla AM;El-Nashar S;Famuyide AO;Subramaniam M;Hawse JR;Khazaie K;Daftary GS
子宫内膜异位症是一种高度流行、慢性、异质性、纤维炎症性疾病，传统治疗仍难以奏效。我们以前的研究表明，KLF 11（一种与子宫疾病有关的转录因子）的缺失会导致子宫内膜异位症的进展。尽管存在广泛的同源性、共表达和人类疾病相关性，但与Klf 11缺失所见的纤维化进展相比，ParkinsKlf 10的缺失导致独特的炎性囊性子宫内膜异位症表型。我们在这里首次确定了KLF 10在子宫内膜异位症中的新作用。在动物子宫内膜异位症模型中，与野生型对照组不同，Klf 10 −/−动物出现囊性病变，伴有大量免疫浸润和极轻微的病变周围纤维化。Klf 10 −/−疾病进展表型也与Klf 11 −/−动物中观察到的多产纤维化和最小免疫细胞浸润形成对比。我们进一步发现，病变基因型，而不是主机决定每个独特的疾病进展表型。在机制上，KLF 10调节CD 40/CD 154介导的免疫途径。炎症和纤维化表型都是慢性纤维炎性疾病如子宫内膜异位症最常见的临床表现。因此，互补的、旁系同源的Klf 10和Klf 11模型为疾病相关背景下的炎症和纤维化机制提供了新的见解。我们的数据表明，在潜在的基因失调的分歧，关键决定了疾病的表型优势，而不是传统的范式炎症是纤维化瘢痕的先例。因此，临床进展和治疗反应中的异质性可能来自不同的基因调控谱。疾病表型相关基因失调的表征为开发复发性和难治性慢性疾病的靶向、个体化治疗提供了新的方法。
Endometriosis is a highly prevalent, chronic, heterogeneous, fibro-inflammatory disease that remains recalcitrant to conventional therapy. We previously showed that loss of KLF11, a transcription factor implicated in uterine disease, results in progression of endometriosis. Despite extensive homology, co-expression, and human disease association, loss of the paralog Klf10 causes a unique inflammatory, cystic endometriosis phenotype in contrast to fibrotic progression seen with loss of Klf11. We identify here for the first time a novel role for KLF10 in endometriosis. In an animal endometriosis model, unlike wild-type controls, Klf10−/− animals developed cystic lesions with massive immune infiltrate and minimal peri-lesional fibrosis. The Klf10−/− disease progression phenotype also contrasted with prolific fibrosis and minimal immune cell infiltration seen in Klf11−/− animals. We further found that lesion genotype rather than that of the host determined each unique disease progression phenotype. Mechanistically, KLF10 regulated CD40/CD154-mediated immune pathways. Both inflammatory as well as fibrotic phenotypes are the commonest clinical manifestations in chronic fibro-inflammatory diseases such as endometriosis. The complementary, paralogous Klf10 and Klf11 models therefore offer novel insights into the mechanisms of inflammation and fibrosis in a disease-relevant context. Our data suggests that divergence in underlying gene dysregulation critically determines disease-phenotype predominance rather than the conventional paradigm of inflammation being precedent to fibrotic scarring. Heterogeneity in clinical progression and treatment response are thus likely from disparate gene regulation profiles. Characterization of disease phenotype-associated gene dysregulation offers novel approaches for developing targeted, individualized therapy for recurrent and recalcitrant chronic disease.