Liu Angela Rose, Sarkar Nandini, Cress Jordan D, de Jesus Tristan J, Vadlakonda Ananya, Centore Joshua T, Griffith Alexis D, Rohr Bethany, McCormick Thomas S, Cooper Kevin D, Ramakrishnan Parameswaran
Department of Pathology, Case Western Reserve University, 2103 Cornell Road, Cleveland, Ohio 44106, USA.
Department of Dermatology, Case Western Reserve University, 2109 Adelbert Road, Cleveland, Ohio 44106, USA.
EBioMedicine. 2024 Dec;110:105452. doi: 10.1016/j.ebiom.2024.105452. Epub 2024 Nov 24.
Nuclear factor kappa B (NF-κB) c-Rel is a psoriasis susceptibility locus, however mechanisms underlying c-Rel transactivation during disease are poorly understood. Inflammation in psoriasis can be triggered following Toll-like Receptor 7 (TLR7) signalling in dendritic cells (DCs), and c-Rel is a critical regulator of DC function. Here, we studied the mechanism of TLR7-induced c-Rel-mediated inflammation in DCs.
The overall expression of c-Rel was analysed in skin sections from patients with psoriasis in human transcriptomics datasets as well as the imiquimod-induced psoriasis mouse model. The function of c-Rel in DCs following TLR7 stimulation was determined by c-Rel CRISPR/Cas9 knockout DC2.4 immortalised cells and primary bone marrow derived dendritic cells from c-Rel knockout C57BL6/J mice.
c-Rel is highly expressed in lesional skin of patients with psoriasis and TLR7-induced psoriatic lesions in mice. c-Rel deficiency protected mice from the disease, and specifically compromised TLR7-induced, and not TLR9- or TLR3-induced, inflammation in dendritic cells. Mechanistically, c-Rel deficiency disrupted activating NF-κB dimers and allowed binding of inhibitory NF-κB homodimers to the IL-1β and IL-6 promoters thus inhibiting their expression. This functionally compromises the ability of c-Rel deficient DCs to induce Th17 polarisation, which is critical in psoriasis pathogenesis.
Our findings reveal that c-Rel is a key regulator of TLR7-mediated dendritic cell-dependent inflammation, and that targeting c-Rel-dependent signalling could prove an effective strategy to dampen excessive inflammation in TLR7-related skin inflammation.
A complete list of funding sources that contributed to this study can be found in the Acknowledgements section.
核因子κB（NF-κB）c-Rel是银屑病的一个易感基因座，但疾病期间c-Rel反式激活的潜在机制尚不清楚。银屑病中的炎症可在树突状细胞（DC）中Toll样受体7（TLR7）信号传导后引发，且c-Rel是DC功能的关键调节因子。在此，我们研究了TLR7诱导的c-Rel介导的DC炎症机制。
在人类转录组学数据集的银屑病患者皮肤切片以及咪喹莫特诱导的银屑病小鼠模型中分析c-Rel的整体表达。通过c-Rel CRISPR/Cas9敲除DC2.4永生化细胞以及来自c-Rel敲除C57BL6/J小鼠的原代骨髓来源树突状细胞，确定TLR7刺激后c-Rel在DC中的功能。
c-Rel在银屑病患者的皮损皮肤以及小鼠TLR7诱导的银屑病皮损中高表达。c-Rel缺陷可使小鼠免受该疾病影响，且特异性损害树突状细胞中TLR7诱导而非TLR9或TLR3诱导的炎症。从机制上讲，c-Rel缺陷破坏了激活型NF-κB二聚体，并使抑制型NF-κB同二聚体与IL-1β和IL-6启动子结合，从而抑制它们的表达。这在功能上损害了c-Rel缺陷型DC诱导Th17极化的能力，而Th17极化在银屑病发病机制中至关重要。
我们的研究结果表明，c-Rel是TLR7介导的树突状细胞依赖性炎症的关键调节因子，且靶向c-Rel依赖性信号传导可能是减轻TLR7相关皮肤炎症中过度炎症的有效策略。
促成本研究的完整资金来源清单可在致谢部分找到。
