Mechanical Ventilation Impairs IL-17 Cytokine Family Expression in Ventilator-Associated Pneumonia

• Main Authors: Fien H. R. De Winter, Bart ’s Jongers, Kenny Bielen, Domenico Mancuso, Leen Timbermont, Christine Lammens, Vincent Van averbeke, Jan Boddaert, Omar Ali, Jan Kluytmans, Alexey Ruzin, Surbhi Malhotra-Kumar, Philippe G. Jorens, Herman Goossens, Samir Kumar-Singh
• Format: Article
• Language: English
• Published: MDPI AG 2019-10-01
• Series: International Journal of Molecular Sciences
• Subjects: mechanical ventilation; ventilator-associated pneumonia; vap; <i>pseudomonas aeruginosa</i>; il-17; il-17a; il-22; ifnγ
• Online Access: https://www.mdpi.com/1422-0067/20/20/5072

Mechanical ventilation (MV) is the primary risk factor for the development of ventilator-associated pneumonia (VAP). Besides inducing a pro-inflammatory T-helper (Th)-1 cytokine response, MV also induces an anti-inflammatory Th2 cytokine response, marked by increased IL-4 secretion and reduced bacterial phagocytic capacity of rodent lung macrophages. Since IL-4 is known to downregulate both Th1 and Th17 cytokines, the latter is important in mediating mucosal immunity and combating bacterial and fungal growth, we studied and showed here in a rat model of MV that Th17 cytokines (IL-17A, IL-17F, and IL-22) were significantly upregulated in the lung as a response to different MV strategies currently utilized in clinic. To study whether the increased IL-4 levels are associated with downregulation of the anti-bacterial Th17 cytokines, we subsequently challenged mechanically ventilated rats with an intratracheal inoculation of <i>Pseudomonas aeruginosa</i> (VAP model) and showed a dramatic downregulation of IL-17A, IL-17F, and IL-22, compared to animals receiving the same bacterial burden without MV. For the studied Th1 cytokines (IFNγ, TNFα, IL-6, and IL-1β), only IFNγ showed a significant decrease as a consequence of bacterial infection in mechanically ventilated rats. We further studied IL-17A, the most studied IL-17 family member, in intensive care unit (ICU) pneumonia patients and showed that VAP patients had significantly lower levels of IL-17A in the endotracheal aspirate compared to patients entering ICU with pre-existing pneumonia. These translational data, obtained both in animal models and in humans, suggest that a deficient anti-bacterial Th17 response in the lung during MV is associated with VAP development.