PO.IM02.03 · 免疫学
Toll样受体4缺失在角质形成细胞中缺失一个Ikkalpha等位基因的小鼠中促进细菌负荷和皮肤肿瘤发生
Toll-like receptor 4 deletion promotes bacterial burden and cutaneous tumorigenesis in mice lacking one Ikkalpha allele in keratinocytes
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摘要 Abstract
中文摘要
Toll样受体4（TLR4）是一种细胞外病原体识别受体（PRR），可识别多种病原体和损伤相关分子模式。对人类TCGA数据库的分析揭示了人类皮肤癌中TLR4基因的许多突变。PRR在应对环境和共生细菌升高促成致癌方面的确切功能仍属未知。近期，我们在角质形成细胞中特异性减少Ikka的1岁龄Ikka f/+ K5 Cre小鼠中发现了少量自发性皮肤鳞状细胞癌（SCC）。有趣的是，与Ikka ΔKC/+小鼠相比，Tlr4的敲除在Ikkalpha ΔKC/+；Tlr4 -/-小鼠中增加了SCC的数量和大小，但缩短了SCC发生的潜伏期。从Ikka ΔKC/+和Ikka ΔKC/+；Tlr4 -/-小鼠获得的自发性皮肤SCC均显示野生型（WT）Ikka等位基因的缺失。因此，我们假设角质形成细胞中Ikka的减少改变了皮肤微生物，而Tlr4缺失促进了这一状况，从而导致自发性皮肤SCC增加。事实上，与WT和Tlr4 -/-小鼠的皮肤相比，Ikka ΔKC/+和Ikka ΔKC/+；Tlr4 -/-小鼠皮肤中的细菌负荷增加，主要为革兰氏阳性厚壁菌。此外，我们利用源自这些小鼠的皮肤类器官探索了细菌与其宿主之间的相互作用。类器官是重现器官上皮层的三维结构，连接了体外和体内模型之间的鸿沟。感染热灭活革兰氏阳性细菌的皮肤类器官显示，Ikka ΔKC/+；Tlr4 -/-中有更多DNA损伤，同时这些小鼠中细菌清除受损。总之，这些发现提示细菌增加导致基因组不稳定，进而导致DNA损伤。此外，我们正在研究哪些细菌通路通过Ikka减少或Ikka减少/Tlr4缺失损害皮肤基因组的完整性，以及Tlr4缺失是否影响免疫细胞在对抗细菌感染中的功能。
查看英文原文 English abstract
Toll-like receptor 4 (TLR4) is an extracellular pathogen recognition receptor (PRR) that identifies a variety of pathogens and damage-associated molecular patterns. Analysis of human TCGA database reveals many mutations of the Toll-Like Receptor 4 ( TLR4 ) gene in human skin cancers. The exact function of PRRs in response to elevated ambient and commensal bacteria for carcinogenesis is still unknown. Recently, we found a low number of spontaneous skin squamous cell carcinomas (SCCs) in 1-year-old Ikka f/+ K5 Cre mice with specific Ikka reduction in keratinocytes. Interestingly, ablation of Tlr4 enhanced SCC numbers and sizes but reduced the latency of SCC development in Ikkalpha Δ KC /+ ; Tlr4 -/- mice compared to Ikka Δ KC/+ mice. Both spontaneous skin SCCs obtained from Ikka Δ KC/+ and Ikka Δ KC/+ ; Tlr4 -/- mice showed loss of wild-type (WT) Ikka allele. Thus, we hypothesize that Ikka reduction in keratinocytes alters skin microbes and Tlr4 deletion promote this condition, which lead to increased spontaneous skin SCCs. Indeed, the bacterial burden were increased in the skin of Ikka Δ KC/+ and Ikka Δ KC/+ ; Tlr4 -/- mice compared to the skin of WT and Tlr4 -/- mice predominately Gram (+) firmicutes. Further, we explore the interactions between bacteria and their hosts using skin organoids derived from these mice. Organoids are three dimensional structures recapitulating the organ's epithelial layer, linking the gap between in vitro and in vivo models. Skin organoids infected with heat killed gram positive bacteria reveals more DNA damage in the Ikka Δ KC/+ ; Tlr4 -/- along with impaired bacteria clearance in these mice . Together, these findings suggest that increased bacteria cause genomic instability which leads to DNA damage. Additionally, we are investigating which bacterial pathways compromise the integrity of the skin genome through Ikka reduction or Ikka reduction/Tlr4 deletion, as well as whether Tlr4 deletion affects immune cell function in combat against bacterial infections.
利益披露 Disclosure
D. Yadav, None.