Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Cell Rep. 2024 Mar 26;43(3):113852. doi: 10.1016/j.celrep.2024.113852. Epub 2024 Feb 29.
The NLRP3 inflammasome is essential for caspase-1 activation and the release of interleukin (IL)-1β, IL-18, and gasdermin-D in myeloid cells. However, research on species-specific NLRP3's physiological impact is limited. We engineer mice with the human NLRP3 gene, driven by either the human or mouse promoter, via syntenic replacement at the mouse Nlrp3 locus. Both promoters facilitate hNLRP3 expression in myeloid cells, but the mouse promoter responds more robustly to LPS. Investigating the disease impact of differential NLRP3 regulation, we introduce the D305N gain-of-function mutation into both humanized lines. Chronic inflammation is evident with both promoters; however, CNS outcomes vary significantly. Despite poor response to LPS, the human promoter results in D305N-associated aseptic meningitis, mirroring human pathology. The mouse promoter, although leading to increased CNS expression post-LPS, does not induce meningitis in D305N mutants. Therefore, human-like NLRP3 expression may be crucial for accurate modeling of its role in disease pathogenesis.
NLRP3 炎性小体对于半胱氨酸蛋白酶-1 的激活以及白细胞介素（IL）-1β、IL-18 和 Gasdermin-D 在髓样细胞中的释放至关重要。然而，关于种属特异性 NLRP3 的生理影响的研究还很有限。我们通过在小鼠 Nlrp3 基因座上进行同基因替换，用人类或小鼠启动子驱动的人 NLRP3 基因对小鼠进行工程改造。这两个启动子都能促进髓样细胞中 hNLRP3 的表达，但小鼠启动子对 LPS 的反应更强烈。为了研究 NLRP3 调节的差异对疾病的影响，我们在这两个人源化系中引入了 D305N 功能获得性突变。尽管两个启动子都有慢性炎症，但中枢神经系统的结果却有显著差异。尽管对 LPS 的反应不佳，但人类启动子导致 D305N 相关的无菌性脑膜炎，与人类病理学相似。尽管在 LPS 后小鼠启动子导致中枢神经系统表达增加，但 D305N 突变体不会引发脑膜炎。因此，类似人类的 NLRP3 表达可能对准确模拟其在疾病发病机制中的作用至关重要。
