The TLR4-MyD88-NF-κB pathway is involved in sIgA-mediated IgA nephropathy.
The TLR4-MyD88-NF-κB pathway is involved in sIgA-mediated IgA nephropathy.
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DOI：
10.1007/s40620-020-00722-3
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发表时间：
2020-12
影响因子：
3.4
通讯作者：
Quan S
中科院分区：
文献类型：
--
作者：
Zhang J;Mi Y;Zhou R;Liu Z;Huang B;Guo R;Wang P;Lu Y;Zhou Y;Quan S
以往的研究表明，分泌型伊加（sIgA）在伊加肾病（IgAN）的免疫应答中起重要作用。Toll样受体（TLRs），尤其是参与粘膜免疫的TLR 4，可能参与IgAN的发病。本研究的目的是调查是否sIgA和TLR 4相互作用介导的IgAN患者的肾损伤。采用免疫荧光法筛选肾组织sIgA沉积阳性的IgAN患者。收集患者唾液sIgA（P-sIgA），并通过jacalin亲和层析进行纯化。来自健康志愿者的唾液sIgA用作对照（N-sIgA）。免疫组化法检测IgA肾病患者肾小球系膜区TLR 4、MyD 88、NF-κB、TNF-α、IL-6、MCP-1的表达，sIgA阳性者表达水平高于sIgA阴性者。体外培养人肾系膜细胞（HRMCs），流式细胞仪检测显示P-sIgA与HRMCs的结合能力明显强于N-sIgA。与N-sIgA组相比，P-sIgA组HRMCs TLR 4表达增强，TNF-α、IL-6和MCP-1分泌增加，MyD 88/NF-κB表达增加。TLR 4 shRNA沉默和NF-κB抑制均降低HRMCs合成TNF-α、IL-6和MCP-1的能力。我们的研究结果表明，sIgA可以诱导TLR 4在HRMCs的高表达，并进一步激活下游信号通路，促使HRMCs分泌多种细胞因子，从而介导IgAN患者的肾损伤。
Previous studies have shown that secretory IgA (sIgA) was critically involved in IgA nephropathy (IgAN) immune responses. Toll-like receptors (TLRs), especially TLR4 which participates in mucosal immunity, may be involved in the pathogenesis of IgAN. The purpose of this study was to investigate whether sIgA and TLR4 interact to mediate kidney damage in IgAN patients. IgAN patients with positive sIgA deposition in renal tissues were screened by immunofluorescence assay. Patient salivary sIgA (P-sIgA) was collected and purified by jacalin affinity chromatography. Salivary sIgA from healthy volunteers was used as a control (N-sIgA). Expression of TLR4, MyD88, NF-κB, TNF-α, IL-6, and MCP-1 were detected in the mesangial area of IgAN patients by immunohistochemistry, the expression levels in patients with positive sIgA deposition were higher than that with negative sIgA deposition. Human renal mesangial cells (HRMCs) were cultured in vitro, flow cytometry showed that P-sIgA bound HRMCs significantly better than N-sIgA. HRMCs were cultured in the presence of sIgA (400 μg/mL) for 24 h, compared with cells cultured with N-sIgA, HRMCs cultured in vitro with P-sIgA showed enhanced expression of TLR4, increased secretion of TNF-α, IL-6, and MCP-1, and increased expression of MyD88/NF-κB. TLR4 shRNA silencing and NF-κB inhibition both reduced the ability of HRMCs to synthesize TNF-α, IL-6, and MCP-1. Our results indicate that sIgA may induce high expression of TLR4 in HRMCs and further activate downstream signalling pathways, prompting HRMCs to secrete multiple cytokines and thereby mediating kidney damage in IgAN patients.
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影响因子：
13.2
作者：
Ashizawa, M;Miyazaki, M;Kohno, S
通讯作者：
Kohno, S
IgA肾病的新风险基因座的发现暗示了与肠道病原体免疫有关的基因。
影响因子：
30.8
作者：
Kiryluk, Krzysztof;Li, Yifu;Scolari, Francesco;Sanna-Cherchi, Simone;Choi, Murim;Verbitsky, Miguel;Fasel, David;Lata, Sneh;Prakash, Sindhuri;Shapiro, Samantha;Fischman, Clara;Snyder, Holly J.;Appel, Gerald;Izzi, Claudia;Viola, Battista Fabio;Dallera, Nadia;Del Vecchio, Lucia;Barlassina, Cristina;Salvi, Erika;Bertinetto, Francesca Eleonora;Amoroso, Antonio;Savoldi, Silvana;Rocchietti, Marcella;Amore, Alessandro;Peruzzi, Licia;Coppo, Rosanna;Salvadori, Maurizio;Ravani, Pietro;Magistroni, Riccardo;Ghiggeri, Gian Marco;Caridi, Gianluca;Bodria, Monica;Lugani, Francesca;Allegri, Landino;Delsante, Marco;Maiorana, Mariarosa;Magnano, Andrea;Frasca, Giovanni;Boer, Emanuela;Boscutti, Giuliano;Ponticelli, Claudio;Mignani, Renzo;Marcantoni, Carmelita;Di Landro, Domenico;Santoro, Domenico;Pani, Antonello;Polci, Rosaria;Feriozzi, Sandro;Chicca, Silvana;Galliani, Marco;Gigante, Maddalena;Gesualdo, Loreto;Zamboli, Pasquale;Battaglia, Giovanni Giorgio;Garozzo, Maurizio;Maixnerova, Dita;Tesar, Vladimir;Eitner, Frank;Rauen, Thomas;Floege, Juergen;Kovacs, Tibor;Nagy, Judit;Mucha, Krzysztof;Paczek, Leszek;Zaniew, Marcin;Mizerska-Wasiak, Malgorzata;Roszkowska-Blaim, Maria;Pawlaczyk, Krzysztof;Gale, Daniel;Barratt, Jonathan;Thibaudin, Lise;Berthoux, Francois;Canaud, Guillaume;Boland, Anne;Metzger, Marie;Panzer, Ulf;Suzuki, Hitoshi;Goto, Shin;Narita, Ichiei;Caliskan, Yasar;Xie, Jingyuan;Hou, Ping;Chen, Nan;Zhang, Hong;Wyatt, Robert J.;Novak, Jan;Julian, Bruce A.;Feehally, John;Stengel, Benedicte;Cusi, Daniele;Lifton, Richard P.;Gharavi, Ali G.
通讯作者：
Gharavi, Ali G.
影响因子：
13.6
作者：
Choi, Mira;Schreiber, Adrian;Kettritz, Ralph
通讯作者：
Kettritz, Ralph
影响因子：
3.4
作者：
Ciferska, Hana;Honsova, Eva;Maixnerova, Dita
通讯作者：
Maixnerova, Dita
影响因子：
13.6
作者：
Feehally, John;Farrall, Martin;Ratcliffe, Peter J.
通讯作者：
Ratcliffe, Peter J.