Autophagy has recently been recognized as a key player in innate and acquired immune responses. Disruption of autophagy in macrophages, the first line of cells in host defense, leads to increased inflammation and bacterial survival. We found that macrophages harboring a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel have weak autophagy activity and are unable to clear some bacteria such as Burkholderia cenocepacia. Mutations in the cftr gene lead to cystic fibrosis, the most common inherited lethal disease among Caucasians. CF patients are born with innate immune deficiency rendering them prone to Staphylococcus aureus, Pseudomonas aeruginosa and Burkholderia cenocepacia. These infections lead to excessive inflammation and the eventual loss of pulmonary function. Notably, all three microbes are controlled by autophagy in healthy immune cells. Our recent studies demonstrated that macrophages from CF patients have weak autophagy activity. It is not clear how the malfunction of an ion channel transporter compromises autophagy. This proposal will identify (i) the role of CFTR ion channel in controlling autophagy in macrophages, and (ii) the role of CFTR in epigenetic regulation of autophagy genes to restore autophagy and innate immunity. This proposal will help in the understanding of basic biological mechanisms linking ion transport to autophagy and also offer new therapeutic targets for CF patients.
The basic biological functions of ion channels have been well studied in epithelial cells but not immune cells such as macrophages. Only recently, that we recognize that reduced functions of an ion channel diminishes the ability of macrophages to combat infection, execute autophagy response and control inflammation. Our study will apply to disease conditions that are characterized by weak autophagy activity such as Crohn's diseases, neurodegenerative disorders and senescence.
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