Deficiency of inhibitory TLR4 homolog RP105 exacerbates fibrosis.
Deficiency of inhibitory TLR4 homolog RP105 exacerbates fibrosis.
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DOI：
10.1172/jci.insight.160684
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发表时间：
2022-11-08
期刊：
影响因子：
8
通讯作者：
Bhattacharyya, Swati
中科院分区：
文献类型：
--
作者：
Wang, Wenxia;Bale, Swarna;Yalavarthi, Bharath;Verma, Priyanka;Tsou, Pei-Suen;Calderone, Ken M.;Bhattacharyya, Dibyendu;Fisher, Gary J.;Varga, John;Bhattacharyya, Swati
TLR4通过其同源损伤相关分子模式(DAMP)激活可在系统性硬化症(SSC)中诱导强大的促纤维化作用和肌成纤维细胞激活，而TLR4或其DAMPS的基因靶向在小鼠中加速纤维化的消退。为了防止异常的DAMP/TLR4活性，进化出了各种负调控因子来抑制信号的幅度和持续时间。其中包括辐射防护105 kDa(RP105)，一种跨膜TLR4同系物，竞争性地抑制TLR4的抑制识别，阻断免疫细胞中的TLR4信号。RP105在SSC依赖TLR4的纤维化反应中的作用尚不清楚。通过对皮肤活检组织进行无偏转录组分析，我们发现TLR4及其接头蛋白MD2在SSC皮肤中的表达水平均升高，且两者之间存在显著的相关性。RP105的表达与SSC的肌成纤维细胞分化程度呈负相关。重要的是，RP105-TLR4的关联性降低，而TLR4-TLR4在SSC患者的成纤维细胞中显示出很强的关联性，这一点在聚乳酸检测中得到了证明。此外，RP105接头MD1在SSC皮肤活检组织和移植的SSC皮肤成纤维细胞中的表达显著降低。外源性RP105-MD1被取消，而RP105的缺失夸大了纤维化的细胞反应。重要的是，在补充性疾病模型中，在小鼠中消融RP105与TLR4信号增强和加重皮肤纤维化有关。因此，我们认为RP105-MD1是TLR4-MD2驱动的持续成纤维细胞激活的一种新的细胞内在负调节因子，代表了控制纤维化过程的关键调控网络。SSC中RP105功能受损可能与疾病的持续进展有关。
Activation of TLR4 by its cognate damage-associated molecular patterns (DAMPs) elicits potent profibrotic effects and myofibroblast activation in systemic sclerosis (SSc), while genetic targeting of TLR4 or its DAMPs in mice accelerates fibrosis resolution. To prevent aberrant DAMP/TLR4 activity, a variety of negative regulators evolved to dampen the magnitude and duration of the signaling. These include radioprotective 105 kDa (RP105), a transmembrane TLR4 homolog that competitively inhibits DAMP recognition of TLR4, blocking TLR4 signaling in immune cells. The role of RP105 in TLR4-dependent fibrotic responses in SSc is unknown. Using unbiased transcriptome analysis of skin biopsies, we found that levels of both TLR4 and its adaptor protein MD2 were elevated in SSc skin and significantly correlated with each other. Expression of RP105 was negatively associated with myofibroblast differentiation in SSc. Importantly, RP105-TLR4 association was reduced, whereas TLR4-TLR4 showed strong association in fibroblasts from patients with SSc, as evidenced by PLA assays. Moreover, RP105 adaptor MD1 expression was significantly reduced in SSc skin biopsies and explanted SSc skin fibroblasts. Exogenous RP105-MD1 abrogated, while loss of RP105 exaggerated, fibrotic cellular responses. Importantly, ablation of RP105 in mice was associated with augmented TLR4 signaling and aggravated skin fibrosis in complementary disease models. Thus, we believe RP105-MD1 to be a novel cell-intrinsic negative regulator of TLR4-MD2–driven sustained fibroblast activation, representing a critical regulatory network governing the fibrotic process. Impaired RP105 function in SSc might contribute to persistence of progression of the disease.
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影响因子：
6.5
作者：
Pendergrass, Sarah A.;Lemaire, Raphael;Francis, Ian P.;Mahoney, J. Matthew;Lafyatis, Robert;Whitfield, Michael L.
通讯作者：
Whitfield, Michael L.
骨髓分化蛋白1保护心肌功能免受高脂肪刺激引起的病理重塑
影响因子：
5.3
作者：
Shen, Cai-Jie;Kong, Bin;Huang, He
通讯作者：
Huang, He
影响因子：
3.6
作者：
Bezhaeva T;Karper J;Quax PHA;de Vries MR
通讯作者：
de Vries MR
影响因子：
5
作者：
Jiang, Xiaobo;Kong, Bin;Huang, He
通讯作者：
Huang, He
DOI：
10.1007/978-1-4939-2929-0_6
发表时间：
2015-01-01
期刊：
METHODS IN MOUSE ATHEROSCLEROSIS
影响因子：
--
作者：
Pineda-Torra, Ines;Gage, Matthew;Pello, Oscar M.
通讯作者：
Pello, Oscar M.