TNFR2 Depletion Reduces Psoriatic Inflammation in Mice by Downregulating Specific Dendritic Cell Populations in Lymph Nodes and Inhibiting IL-23/IL-17 Pathways.
TNFR2 Depletion Reduces Psoriatic Inflammation in Mice by Downregulating Specific Dendritic Cell Populations in Lymph Nodes and Inhibiting IL-23/IL-17 Pathways.
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TNFR2缺失通过下调淋巴结中特定的树突状细胞数量和抑制IL-23/IL-17途径来减轻银屑病小鼠的炎症。
DOI：
10.1016/j.jid.2021.12.036
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发表时间：
2022-08
影响因子：
6.5
通讯作者：
Husni, M. Elaine
中科院分区：
文献类型：
--
作者：
Chandrasekharan, Unnikrishnan M.;Kaur, Raminderjit;Harvey, Jennifer E.;Braley, Chad;Rai, Vandana;Lee, MacKenzie;de Windt, Nicholas;Hsieh, Jason;Jaini, Ritika;Bayik, Defne;Scheraga, Rachel G.;Fernandez, Anthony P.;DiCorleto, Paul E.;Husni, M. Elaine
肿瘤坏死因子-α是一种促炎症细胞因子，是银屑病发病的重要介质。肿瘤坏死因子-α通过激活肿瘤坏死因子-α受体1和肿瘤坏死因子受体2发挥作用。抗肿瘤坏死因子药物中和肿瘤坏死因子-α，从而阻断肿瘤坏死因子受体1和肿瘤坏死因子受体2的激活，已被证明对银屑病有很高的疗效。肿瘤坏死因子-α在宿主防御中也起着重要作用；因此，抗肿瘤坏死因子治疗可能会导致潜在的严重不良反应，包括机会性感染和潜在的结核病复活。这些不良反应归因于TNFR1失活。因此，了解肿瘤坏死因子受体1和肿瘤坏死因子受体2的相对作用对于缓解银屑病与全局阻断肿瘤坏死因子-α具有临床意义。我们发现，在咪喹莫特牛皮癣(ImQ)模型中，TNFR2基因敲除(TNFR2KO)小鼠的表皮增生、特征性大体皮损和IL-23或IL-17A水平显著减少，但在TNFR1KO小鼠中没有。此外，ImQ介导的引流淋巴结髓系树突状细胞(MDC)、产生肿瘤坏死因子/诱导型一氧化氮合酶的树突状细胞(Tip-DC)和IL-23表达的增加依赖于TNFR2，而不依赖于TNFR1。总之，我们的结果支持银屑病的炎症不依赖于TNFR1的活性，而是由依赖于TNFR2的IL-23/IL-17途径的激活所驱动。因此，以TNFR2通路为靶点可能成为治疗银屑病的新一代潜在方法。
Tumor necrosis factor-α (TNF-α), a proinflammatory cytokine, is a crucial mediator of psoriasis pathogenesis. TNF-α functions by activating TNF-α receptor 1 (TNFR1) and TNFR2. Anti-TNF drugs that neutralize TNF-α, thus blocking the activation of TNFR1 and TNFR2, have been proven highly therapeutic in psoriatic diseases. TNF-α also plays an important role in host defense; thus, anti-TNF therapy can cause potentially serious adverse effects including opportunistic infections and latent tuberculosis reactivation. These adverse effects are attributed to TNFR1 inactivation. Thus, understanding the relative contributions of TNFR1 and TNFR2 has clinical implications in mitigating psoriasis versus global TNF-α blockade. We found a significant reduction in psoriasis lesions as measured by epidermal hyperplasia, characteristic gross skin lesion and IL-23 or IL-17A levels in TNFR2 knockout (TNFR2KO), but not in TNFR1KO mice, in the imiquimod psoriasis (IMQ) model. Further, IMQ-mediated increase in the myeloid dendritic cells (MDC), TNF/iNOS producing DC (Tip-DC) and IL-23 expression, in the draining lymph nodes were dependent on TNFR2, but not TNFR1. Together, our results support that psoriatic inflammation is not dependent on TNFR1 activity but driven by a TNFR2-dependent IL-23/IL-17 pathway activation. Thus, targeting the TNFR2 pathway may emerge as a potential next generation therapeutic approach for psoriatic diseases.
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DOI：
10.1177/039463200902200411
发表时间：
2009-10-01
影响因子：
3.5
作者：
Caldarola, G.;De Simone, C.;Feliciani, C.
通讯作者：
Feliciani, C.
影响因子：
5
作者：
Jacobs, M;Brown, N;Ryffel, B
通讯作者：
Ryffel, B
影响因子：
4.1
作者：
Arce-Sillas A;Álvarez-Luquín DD;Tamaya-Domínguez B;Gomez-Fuentes S;Trejo-García A;Melo-Salas M;Cárdenas G;Rodríguez-Ramírez J;Adalid-Peralta L
通讯作者：
Adalid-Peralta L
影响因子：
15.9
作者：
Keeton, Roanne;Allie, Nasiema;Jacobs, Muazzam
通讯作者：
Jacobs, Muazzam
影响因子：
120.7
作者：
Gottenberg, Jacques-Eric;Brocq, Olivier;Ravaud, Philippe
通讯作者：
Ravaud, Philippe