Anavex Life Sciences Corp (AVXL)

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Anavex 2-73 and/or Anavex 3-71 for the treatment of cystic fibrosis

Metabolic Reprograming of Cystic Fibrosis Macrophages via the IRE1a Arm of the Unfolded Protein Response Results in Exacerbated Inflammation.
Lara-Reyna S1,2,3, Scambler T1,3, Holbrook J1,2,3, Wong C1,2,3, Jarosz-Griffiths HH1,2,3, Martinon F3,4, Savic S1,3,5, Peckham D2,3,6, McDermott MF1,3.
Author information
1
Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, United Kingdom.
2
Leeds Institute of Medical Research at St. James's, University of Leeds, Leeds, United Kingdom.
3
Leeds Cystic Fibrosis Trust Strategic Research Centre, University of Leeds, Leeds, United Kingdom.
4
Department of Biochemistry, University of Lausanne, Epalinges, Switzerland.
5
Department of Clinical Immunology and Allergy, St. James's University Hospital, Leeds, United Kingdom.
6
Adult Cystic Fibrosis Unit, St. James's University Hospital, Leeds, United Kingdom.
Abstract
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 IRE1a-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 IRE1a-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 IRE1a, 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 IRE1a-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 IRE1a, may improve the metabolic fitness of macrophages, and other immune cells in CF and other immune-related disorders.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6687873/

Taken together, these results indicate that Sigmar1-dependent activation of IRE1a-XBP1s ER-stress response pathways

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5518542/

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