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Article

Cystic Fibrosis Defective Response to Infection Involves Autophagy and Lipid Metabolism

1
Biochemistry and Molecular Biology Laboratory, Health Science Department, University of Milan, San Paolo Hospital, 20142 Milan, Italy
2
Laboratory of Clinical Microbiology, Health Science Department, University of Milan, San Paolo Hospital, 20142 Milan, Italy
3
National Research Council of Italy, Institute for Biomedical Technologies, Via Fratelli Cervi 93, 20090 Milan, Italy
4
Health Sciences Department, University of Milan, Thoracic surgery and transplantation Unit, Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
5
Department of Clinical Sciences, Section of Biochemistry, Biology and Physics, Polytechnic University of Marche, 60131 Ancona, Italy
6
Cystic Fibrosis Referral Care Center, Mother-Child Department, United Hospitals Le Torrette, 60126 Ancona, Italy
7
“Aldo Ravelli” Center for Neurotechnology and Experimental Brain Therapeutics, via Antonio di Rudinì 8, 20142 Milan, Italy
*
Author to whom correspondence should be addressed.
The authors contributed equally to this work.
Cells 2020, 9(8), 1845; https://doi.org/10.3390/cells9081845
Received: 26 June 2020 / Revised: 31 July 2020 / Accepted: 4 August 2020 / Published: 6 August 2020
Cystic fibrosis (CF) is a hereditary disease, with 70% of patients developing a proteinopathy related to the deletion of phenylalanine 508. CF is associated with multiple organ dysfunction, chronic inflammation, and recurrent lung infections. CF is characterized by defective autophagy, lipid metabolism, and immune response. Intracellular lipid accumulation favors microbial infection, and autophagy deficiency impairs internalized pathogen clearance. Myriocin, an inhibitor of sphingolipid synthesis, significantly reduces inflammation, promotes microbial clearance in the lungs, and induces autophagy and lipid oxidation. RNA-seq was performed in Aspergillusfumigatus-infected and myriocin-treated CF patients’ derived monocytes and in a CF bronchial epithelial cell line. Fungal clearance was also evaluated in CF monocytes. Myriocin enhanced CF patients’ monocytes killing of A. fumigatus. CF patients’ monocytes and cell line responded to infection with a profound transcriptional change; myriocin regulates genes that are involved in inflammation, autophagy, lipid storage, and metabolism, including histones and heat shock proteins whose activity is related to the response to infection. We conclude that the regulation of sphingolipid synthesis induces a metabolism drift by promoting autophagy and lipid consumption. This process is driven by a transcriptional program that corrects part of the differences between CF and control samples, therefore ameliorating the infection response and pathogen clearance in the CF cell line and in CF peripheral blood monocytes. View Full-Text
Keywords: cystic fibrosis; sphingolipids; autophagy; myriocin; Aspergillus fumigatus cystic fibrosis; sphingolipids; autophagy; myriocin; Aspergillus fumigatus
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MDPI and ACS Style

Mingione, A.; Ottaviano, E.; Barcella, M.; Merelli, I.; Rosso, L.; Armeni, T.; Cirilli, N.; Ghidoni, R.; Borghi, E.; Signorelli, P. Cystic Fibrosis Defective Response to Infection Involves Autophagy and Lipid Metabolism. Cells 2020, 9, 1845. https://doi.org/10.3390/cells9081845

AMA Style

Mingione A, Ottaviano E, Barcella M, Merelli I, Rosso L, Armeni T, Cirilli N, Ghidoni R, Borghi E, Signorelli P. Cystic Fibrosis Defective Response to Infection Involves Autophagy and Lipid Metabolism. Cells. 2020; 9(8):1845. https://doi.org/10.3390/cells9081845

Chicago/Turabian Style

Mingione, Alessandra, Emerenziana Ottaviano, Matteo Barcella, Ivan Merelli, Lorenzo Rosso, Tatiana Armeni, Natalia Cirilli, Riccardo Ghidoni, Elisa Borghi, and Paola Signorelli. 2020. "Cystic Fibrosis Defective Response to Infection Involves Autophagy and Lipid Metabolism" Cells 9, no. 8: 1845. https://doi.org/10.3390/cells9081845

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