Interleukin-10 Produced by Myeloid-Derived Suppressor Cells Provides Protection to Carbapenem-ResistantKlebsiella pneumoniaeSequence Type 258 by Enhancing Its Clearance in the Airways

Abstract

Carbapenem-resistant Klebsiella pneumoniae sequence type 258 (CRKP-ST258) can cause chronic infections in lungs and airways, with repeated episodes of bacteremia. In this report we addressed whether the recruitment of myeloid cells producing the anti-inflammatory cytokine interleukin-10 (IL-10) modulates the clearance of CKRP-ST258 in the lungs and establishes bacterial persistence. Our data demonstrate that during pneumonia caused by a clinical isolate of CRKP-ST258 (KP35) there is an early recruitment of monocyte-myeloid-derived suppressor cells (M-MDSCs) and neutrophils that actively produce IL-10. However, M-MDSCs were the cells that sustained the production of IL-10 over the time of infection evaluated. Using mice unable to produce IL-10 (IL-10 Ϫ/Ϫ ), we observed that the production of this cytokine during the infection caused by KP35 is important to control bacterial burden, to prevent lung damage, to modulate cytokine production, and to improve host survival. Importantly, intranasal transfer of bone marrow-derived M-MDSCs from mice able to produce IL-10 at 1 day prior to infection improved the ability of IL-10 Ϫ/Ϫ mice to clear KP35 in the lungs, decreasing their mortality. Altogether, our data demonstrate that IL-10 produced by M-MDSCs is required for bacterial clearance, reduction of lung tissue damage, and host survival during KP35 pneumonia.

Cardiolipin-mediated PPARγ S112 phosphorylation impairs IL-10 production and inflammation resolution during bacterial pneumonia

“…Elevated levels of the mito-DAMP CL have been reported in the lung fluids of patients suffering from severe pneumonia as well as in the murine pneumonia models (Chakraborty et al, 2017;Ray et al, 2010). Several previous studies (Arora et al, 2010;Chakraborty et al, 2017;Peñ aloza et al, 2019;Poe et al, 2013) and our present study have identified lung MDSCs as a major source of IL-10, necessary for lung inflammation resolution ( Figures S1B and S1C). Although previous work showed that CL blocks IL-10 expression through PPARg K107 SUMOylation in lung MDSCs, the precise mechanism remained unexplored (Chakraborty et al, 2017).…”

Immunomodulatory Effects of Lactobacillus plantarum on Inflammatory Response Induced by Klebsiella pneumoniae

“…On the basis of several studies, IL-10 has emerged as a key immunoregulator during respiratory infection (49)(50)(51)(52). A recent study on K. pneumoniae showed that IL-10 is required for bacterial clearance, reduction of lung tissue damage, and host survival (53). Regarding other pulmonary pathogens, Salva et al reported that oral administration of Lactobacillus rhamnosus CRL1505 confers resistance to pulmonary infection by Streptococcus pneumoniae in a mouse model via increased production of IFN-␥, IL-6, IL-4, and IL-10 (33).…”

L-Arginine Enhances Intracellular Killing of Carbapenem-Resistant Klebsiella pneumoniae ST258 by Murine Neutrophils

“…Despite evasion of neutrophilic killing of CRKP-ST258 through different mechanisms, neutrophils still have an important role in CRKP-ST258 clearance in vivo. Neutrophil depletion impairs lung CRKP-ST258 clearance (Ahn et al, 2016) and impaired neutrophil activity can be associated to impaired CRKP-ST258 clearance (Peñaloza et al, 2019b), indicating that in vivo, neutrophils are important cells in CRKP-ST258 clearance. Indeed, CRKP-ST258 phagocytic killing by neutrophils can be improved after antibodymediated opsonization directed against the polysaccharide capsule in vitro (Kobayashi et al, 2018).…”

“…In a previous report, using a representative CRKP-ST258 isolate from New York City (KP35) (Gomez-Simmonds et al, 2015), we characterized the immune response evoked in a murine model of pneumonia. Although neutrophils are rapidly recruited to the lungs, KP35 survive in the lung tissue for at least 10 days post infection (Ahn et al, 2016;Peñaloza et al, 2019b). Along with neutrophils, monocytic myeloid-derived suppressor cells (M-MDSCs) were also rapidly recruited during KP35 pneumonia (Ahn et al, 2016), and the production of IL-10 by these cells promotes a balanced immune response that ultimately aids in the clearance of KP35 from the airways (Peñaloza et al, 2019b).…”

“…Although neutrophils are rapidly recruited to the lungs, KP35 survive in the lung tissue for at least 10 days post infection (Ahn et al, 2016;Peñaloza et al, 2019b). Along with neutrophils, monocytic myeloid-derived suppressor cells (M-MDSCs) were also rapidly recruited during KP35 pneumonia (Ahn et al, 2016), and the production of IL-10 by these cells promotes a balanced immune response that ultimately aids in the clearance of KP35 from the airways (Peñaloza et al, 2019b). These cells suppress the inflammatory response through different mechanisms, including production of IL-10 and depleting L-arginine through the activity of Arginase-1 and iNOS (Peñaloza et al, 2019a).…”