Data_Sheet_1_Metabolic Reprograming of Cystic Fibrosis Macrophages via the IRE1α Arm of the Unfolded Protein Response Results in Exacerbated Inflammation.PDF

Cystic Fibrosis (CF) is a recessive genetic disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). CFTR mutations cause dysregulation of channel function with intracellular accumulation of misfolded proteins and endoplasmic reticulum (ER) stress, with activation of the IRE1α-XBP1 pathway that regulates a subset of unfolded protein response (UPR) genes. This pathway regulates a group of genes that control proinflammatory and metabolic responses in different immune cells; however, the metabolic state of immune cells and the role of this pathway in CF remain elusive. Our results indicate that only innate immune cells from CF patients present increased levels of ER stress, mainly affecting neutrophils, monocytes, and macrophages. An overactive IRE1α-XBP1 pathway reprograms CF M1 macrophages toward an increased metabolic state, with increased glycolytic rates and mitochondrial function, associated with exaggerated production of TNF and IL-6. This hyper-metabolic state, seen in CF macrophages, is reversed by inhibiting the RNase domain of IRE1α, thereby decreasing the increased glycolic rates, mitochondrial function and inflammation. Altogether, our results indicate that innate immune cells from CF patients are primarily affected by ER stress. Moreover, the IRE1α-XBP1 pathway of the UPR is responsible for the hyper-metabolic state seen in CF macrophages, which is associated with the exaggerated inflammatory response. Modulating ER stress, metabolism and inflammation, by targeting IRE1α, may improve the metabolic fitness of macrophages, and other immune cells in CF and other immune-related disorders.

囊性纤维化（CF）是一种由囊性纤维化跨膜电导调节因子（CFTR）基因突变引起的隐性遗传性疾病。CFTR基因突变导致通道功能失调，细胞内错误折叠蛋白积累以及内质网（ER）应激，激活了调节部分未折叠蛋白反应（UPR）基因的IRE1α-XBP1途径。该途径调节一组控制不同免疫细胞中促炎和代谢反应的基因；然而，免疫细胞的代谢状态以及该途径在CF中的作用仍不明确。我们的研究结果指出，仅来自CF患者的固有免疫细胞表现出增高的ER应激水平，主要影响中性粒细胞、单核细胞和巨噬细胞。过度活跃的IRE1α-XBP1途径重编程CF M1巨噬细胞，使其代谢状态增强，糖酵解速率和线粒体功能增加，与TNF和IL-6的过量产生有关。在CF巨噬细胞中观察到的这种过度代谢状态，通过抑制IRE1α的RNase结构域得以逆转，从而降低增高的糖酵解速率、线粒体功能和炎症。总之，我们的研究结果表明，CF患者的固有免疫细胞主要受到ER应激的影响。此外，UPR中的IRE1α-XBP1途径是CF巨噬细胞中观察到的高代谢状态的原因，这与放大的炎症反应相关。通过针对IRE1α调节ER应激、代谢和炎症，可能改善CF及其他免疫相关疾病中巨噬细胞及其他免疫细胞的代谢适应性。