Metabolic Reprogramming of Cystic Fibrosis Macrophages through the Unfolded Protein Response

Cystic fibrosis (CF) is a life-threatening autosomal genetic disease, which affects approximately 48,204 individuals in Europe and 29,887 in the USA. This condition is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). In CF, the mutated CFTR, in the case of DF508, causes accumulation of misfolded proteins leading to endoplasmic reticulum (ER) stress, with activation of the IRE1a-XBP1 pathway. This pathway is essential in the regulation of a subset of genes controlling proinflammatory and metabolic responses in immune cells; nevertheless, the metabolic rates of immune cells and the role of this pathway in CF remain elusive. In this study, it was shown that innate immune cells from patients with CF show significantly higher levels of ER stress, particularly in the IRE1a-XBP1 signalling pathway. Interestingly, ER stress was only present in neutrophils, monocytes and macrophages from patients with CF. Overactivation of the IRE1a-XBP1 signalling pathway rewires M1 macrophages from patients with CF, and increases macrophages’ metabolic rates, with high glycolytic rates and mitochondrial function. The increased activity of the IRE1a-XBP1 signalling pathway and the increased metabolic rates were associated with excessive production of TNF and IL-6. Specific inhibition of the RNase domain of the IRE1 arm decreased the excessive glycolytic rates, mitochondrial function and production of inflammatory cytokines. Furthermore, Orkambi, Symkevi and Ivacaftor had an essential impact in changing the metabolic profile of cells with CF mutations. This study shows how innate immune cells from CF patients are affected by ER stress, in particular, M1 macrophages. Moreover, the IRE1a-XBP1 signalling pathway is essential for the increased metabolic rates seen in M1 macrophages with CF mutations. Modulation of ER stress might be an exciting option to recover the metabolic fitness of cells with CF mutations