Immunometabolism and immunomodulation in the airways:Novel strategies to treat pneumonia

Abstract

In the last decade, the field of immunometabolism has gained a lot of attention and close links have been revealed between cell metabolic programs and the specific immune functions they support. However, studies investigating airway epithelial cell function are scarce and dominated by investigations using cell lines, in which metabolism is intrinsically altered. The overall objective of this thesis is to improve our insight into the regulation of airway immunity upon exposure to respiratory pathogens or components thereof, and thereby to identify potential targets in the airways that can be manipulated in order to enhance immune function. Employing an elegant model of primary human bronchial epithelial cells cultured in the air-liquid interface mimicking the human airways we were able to identify two key nodes regulating the immune response in the airways: mTOR and HIF1α. In addition, we studied the effect of the PPAR-γ agonist pioglitazone in experimental pneumonia in mice caused by Pseudomonas aeruginosa and Klebsiella pneumoniae, tow common human respiratory pathogens. Finally, we report the effect of recombinant IL-33 administration on the host response during murine Klebsiella pneumonia. The results of this thesis identified novel targets to modulate the immune function in the airways. These strategies should be further investigated in order to enable translation to the clinical scene for the treatment of pneumonia. These findings are of special relevance in the era of an increasing incidence of infections caused by antimicrobial resistant bacteria where new therapeutic strategies are urgently needed