Prostaglandin E2 attenuates lung fibroblast differentiation via inactivation of yes-associated protein signaling.
Prostaglandin E2 attenuates lung fibroblast differentiation via inactivation of yes-associated protein signaling.
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前列腺素 E2 通过抑制 yes 相关蛋白信号传导来减弱肺成纤维细胞分化。
DOI：
10.1096/fj.202300745rr
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Paruchuri,Sailaja
中科院分区：
文献类型：
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作者：
Teegala,LakshminarayanReddy;Gudneppanavar,Ravindra;SabuKattuman,EmmaElizabeth;Snyderman,Matthew;Thanusha,AraniVaramuniprasad;Katari,Venkatesh;Thodeti,CharlesK;Paruchuri,Sailaja
前列腺素E_2(PGE_2)参与了肺纤维化过程中转化生长因子β_1对成纤维细胞分化的抑制作用。然而，确切的机制还没有被很好地理解。我们发现PGE_2通过EP2R和EP4R抑制机械感觉分子Lysyl Oxidase like 2、Myocardin相关转录因子A、ECM蛋白、纤溶酶原激活抑制物1(PAI-1)、纤维连接蛋白(FN)、α-平滑肌肌动蛋白(α-SMA)和氧化还原感受器(烟酰胺腺嘌呤二核苷酸磷酸二核苷酸氧化酶4)的表达，这是转化生长因子β1介导的成纤维细胞分化所必需的。我们进一步证明，PGE2通过YAP抑制纤维化信号，但这种作用独立于其对SMAD磷酸化和保守性圆柱瘤病(CyLD；去泛素酶)表达的作用。在机制上，PGE2可使EP2R/GαS下游的YAP磷酸化/失活，并抑制其向核的转位，从而抑制其与茶区家族成员(TeADs)的相互作用和纤维化基因的转录。重要的是，药物或siRNA介导的YAP抑制显著下调转化生长因子β1介导的纤维化基因的表达和肌成纤维细胞的形成。值得注意的是，YAP在D的肺中表达上调。粉尘处理的野生型(WT)小鼠相对于生理盐水处理的WT小鼠。我们的结果揭示了PGE2-YAP相互作用在成纤维细胞分化中的独特作用，并且PGE2/YAP抑制可以作为治疗与哮喘等肌成纤维细胞相关的病理疾病的新的治疗靶点。
Prostaglandin E2(PGE2) has been implicated in counteracting fibroblast differentiation by TGFβ1 during pulmonary fibrosis. However, the precise mechanism is not well understood. We show here that PGE2via EP2R and EP4R inhibits the expression of mechanosensory molecules Lysyl Oxidase Like 2 (LOXL2), myocardin‐related transcription factor A (MRTF‐A), ECM proteins, plasminogen activation inhibitor 1 (PAI‐1), fibronectin (FN), α‐smooth muscle actin (α‐SMA), and redox sensor (nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (NOX4)) required for TGFβ1‐mediated fibroblast differentiation. We further demonstrate that PGE2inhibits fibrotic signaling via Yes‐associated protein (YAP) but does so independently from its actions on SMAD phosphorylation and conserved cylindromatosis (CYLD; deubiquitinase) expression. Mechanistically, PGE2phosphorylates/inactivates YAP downstream of EP2R/Gαs and restrains its translocation to the nucleus, thus inhibiting its interaction with TEA domain family members (TEADs) and transcription of fibrotic genes. Importantly, pharmacological or siRNA‐mediated inhibition of YAP significantly downregulates TGFβ1‐mediated fibrotic gene expression and myofibroblast formation. Notably, YAP expression is upregulated in the lungs ofD. farinae‐treated wild type (WT) mice relative to saline‐treated WT mice. Our results unravel a unique role for PGE2‐YAP interactions in fibroblast differentiation, and that PGE2/YAP inhibition can be used as a novel therapeutic target in the treatment of pathological conditions associated with myofibroblasts like asthma.