Dysregulated signalling pathways in innate immune cells with cystic fibrosis mutations
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Cellular and Molecular Life Sciences
REVIEW
Dysregulated signalling pathways in innate immune cells with cystic fibrosis mutations Samuel Lara‑Reyna1,2,3 · Jonathan Holbrook1,2,3 · Heledd H. Jarosz‑Griffiths2,3 · Daniel Peckham2,3,4 · Michael F. McDermott1,3 Received: 4 March 2020 / Revised: 22 April 2020 / Accepted: 24 April 2020 © The Author(s) 2020
Abstract Cystic fibrosis (CF) is one of the most common life-limiting recessive genetic disorders in Caucasians, caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). CF is a multi-organ disease that involves the lungs, pancreas, sweat glands, digestive and reproductive systems and several other tissues. This debilitating condition is associated with recurrent lower respiratory tract bacterial and viral infections, as well as inflammatory complications that may eventually lead to pulmonary failure. Immune cells play a crucial role in protecting the organs against opportunistic infections and also in the regulation of tissue homeostasis. Innate immune cells are generally affected by CFTR mutations in patients with CF, leading to dysregulation of several cellular signalling pathways that are in continuous use by these cells to elicit a proper immune response. There is substantial evidence to show that airway epithelial cells, neutrophils, monocytes and macrophages all contribute to the pathogenesis of CF, underlying the importance of the CFTR in innate immune responses. The goal of this review is to put into context the important role of the CFTR in different innate immune cells and how CFTR dysfunction contributes to the pathogenesis of CF, highlighting several signalling pathways that may be dysregulated in cells with CFTR mutations. Keywords Cystic fibrosis · Inflammation · Neutrophils · Monocytes · Macrophages · CFTR and autoinflammation
Introduction: an overview of cystic fibrosis Cystic fibrosis (CF) is one of the most common life-threatening autosomal recessive genetic diseases in Caucasians, affecting approximately 48,000 individuals in Europe and 30,000 in the USA [1, 2]. This condition is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR), which is a transmembrane ion channel highly * Samuel Lara‑Reyna [email protected] * Michael F. McDermott [email protected] 1
Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds LS9 7TF, UK
2
Leeds Institute of Medical Research at St James’s, University of Leeds, Leeds LS9 7TF, UK
3
Leeds Cystic Fibrosis Trust Strategic Research Centre, University of Leeds, Leeds LS9 7TF, UK
4
Adult Cystic Fibrosis Unit, St James’s University Hospital, Leeds LS9 7TF, UK
expressed by cells of the respiratory, digestive and male urogenital tracts [3–8]. Epithelial and secretory cells are known to be profoundly affected by CFTR mutations, due to altered physiological function as a result of abnormal production, maturation and function of the CFTR protein and aberrations in ion transport, most importantly chl
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