Department of Immunology and.
Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
JCI Insight. 2024 Jul 23;9(16):e178563. doi: 10.1172/jci.insight.178563.
Loss of NADPH oxidase (NOX2) exacerbates systemic lupus erythematosus (SLE) in mice and humans, but the mechanisms underlying this effect remain unclear. To identify the cell lineages in which NOX2 deficiency drives SLE, we employed conditional KO and chimeric approaches to delete Cybb in several hematopoietic cell lineages of MRL.Faslpr SLE-prone mice. Deletion of Cybb in macrophages/monocytes exacerbated SLE nephritis, though not to the degree observed in the Cybb global KOs. Unexpectedly, the absence of Cybb in B cells resulted in profound glomerulonephritis and interstitial nephritis, rivaling that seen with global deletion. Furthermore, we identified that NOX2 is a key regulator of TLR7, a driver of SLE pathology, both globally and specifically in B cells. This is mediated in part through suppression of TLR7-mediated NF-κB signaling in B cells. Thus, NOX2's immunomodulatory effect in SLE is orchestrated not only by its function in the myeloid compartment, but through a pivotal role in B cells by selectively inhibiting TLR7 signaling.
NADPH 氧化酶（NOX2）缺失会加重系统性红斑狼疮（SLE）在小鼠和人类中的发病，但其具体作用机制尚不清楚。为了明确 NOX2 缺失导致 SLE 的细胞谱系，我们采用条件性 KO 和嵌合方法，在 MRL.Faslpr 狼疮易感小鼠的几种造血细胞谱系中敲除 Cybb。巨噬细胞/单核细胞中 Cybb 的缺失加重了狼疮肾炎，但不如 Cybb 全局 KO 观察到的那样严重。出乎意料的是，B 细胞中 Cybb 的缺失导致严重的肾小球肾炎和间质性肾炎，与全局缺失时的情况相当。此外，我们发现，NOX2 是 TLR7 的关键调节因子，TLR7 是 SLE 发病机制的驱动因素，在全局和特定的 B 细胞中均如此。这部分是通过抑制 B 细胞中 TLR7 介导的 NF-κB 信号转导来介导的。因此，NOX2 在 SLE 中的免疫调节作用不仅与其在髓系细胞中的功能有关，而且通过在 B 细胞中选择性抑制 TLR7 信号转导，发挥关键作用。
