Department of Pediatrics, Yale University School of Medicine, New Haven, CT 06509, USA.
J Immunol. 2011 Jun 15;186(12):6990-8. doi: 10.4049/jimmunol.1100396. Epub 2011 May 18.
Morbidity and mortality in cystic fibrosis (CF) are due not only to abnormal epithelial cell function, but also to an abnormal immune response. We have shown previously that macrophages lacking CF transmembrane conductance regulator (CFTR), the gene mutated in CF, contribute significantly to the hyperinflammatory response observed in CF. In this study, we show that lack of functional CFTR in murine macrophages causes abnormal TLR4 subcellular localization. Upon LPS stimulation, CFTR macrophages have prolonged TLR4 retention in the early endosome and reduced translocation into the lysosomal compartment. This abnormal TLR4 trafficking leads to increased LPS-induced activation of the NF-κB, MAPK, and IFN regulatory factor-3 pathways and decreased TLR4 degradation, which affects downregulation of the proinflammatory state. In addition to primary murine cells, mononuclear cells isolated from CF patients demonstrate similar defects in response to LPS. Moreover, specific inhibition of CFTR function induces abnormal TLR4 trafficking and enhances the inflammatory response of wild-type murine cells to LPS. Thus, functional CFTR in macrophages influences TLR4 spatial and temporal localization and perturbs LPS-mediated signaling in both murine CF models and patients with CF.
囊性纤维化（CF）患者的发病率和死亡率不仅与上皮细胞功能异常有关，还与异常的免疫反应有关。我们之前已经表明，缺乏囊性纤维化跨膜电导调节因子（CFTR）的巨噬细胞（CFTR 基因突变导致 CF 发生）会显著促进 CF 中观察到的过度炎症反应。在这项研究中，我们表明，鼠巨噬细胞中缺乏功能性 CFTR 会导致 TLR4 亚细胞定位异常。在 LPS 刺激下，CFTR 巨噬细胞中 TLR4 在早期内体中的滞留时间延长，进入溶酶体区室的转移减少。这种异常的 TLR4 运输导致 LPS 诱导的 NF-κB、MAPK 和 IFN 调节因子-3 途径的激活增加，以及 TLR4 降解减少，从而影响促炎状态的下调。除了原代鼠细胞外，从 CF 患者中分离的单核细胞对 LPS 的反应也表现出类似的缺陷。此外，CFTR 功能的特异性抑制会诱导 TLR4 运输异常，并增强野生型鼠细胞对 LPS 的炎症反应。因此，巨噬细胞中功能性 CFTR 会影响 TLR4 的空间和时间定位，并扰乱 CF 两种鼠模型和 CF 患者中 LPS 介导的信号转导。
