Flagellin-induced generation of myeloid-derived suppressor cells: functionality and relevance for cystic fibrosis lung disease
African, American and Oceania Studies
Final Report Abstract
MDSC generation and functionalities have been studied thoroughly in several types of cancer, yet their regulation and functional role in infectious disease conditions remained poorly defined. Here we studied the role of MDSCs in the setting of airway P. aeruginosa infection, which is highly relevant for several human diseases, particularly Cystic Fibrosis (CF), COPD, ventilation-associated pneumonia and burnrelated infections.CF is a monogenetic disease caused by mutations in the gene encoding for the chloride channel Cystic Fibrosis Transmembrane Conductance Regulator (CFTR). Morbidity and mortality of CF patients is mainly due to a steady decline in the lung function, caused by infections and hyperinflammatory immune responses leading to lung injury. Pseudomonas aeruginosa, a gram-negative flagellated opportunistic pathogen, is the most common pathogen causing chronic infections and leading to severe problems in CF patients. Previous studies from our group revealed that MDSC numbers are increased in CF patients, especially in patients with chronic P. aeruginosa infections and correlated with better lung function. In this study we investigated the interaction of P. aeruginosa and MDSCs as well as assessed the impact of CFTR deficiency. Therefore we performed in vivo acute pulmonary infections in wildtype as well as in Cftr-/- mice followed by flow cytometry (FACS) analysis to quantify MDSCs in different tissues. We could demonstrate that acute pulmonary P. aeruginosa infections potently induce CD11b+ Ly6G+ Ly6C-low cells. These markers describe the profile of granulocytic/ neutrophilic MDSCs (G-MDSCs). In vitro expansion of wildtype or Cftr-/- splenocytes with granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-6 (IL-6) also resulted in the induction of CD11b+ Ly6G+ Ly6C-low cells. To check for their suppressive nature and thereby distinguish the induced CD11b+ Ly6G+ Ly6C-low cells from neutrophilic granulocytes, we isolated the cells and assessed their suppressive capability using CFSE based T cell proliferation assays. The isolated CD11b+ Ly6G+ Ly6C-low cells from lungs, spleens, bone marrow and bronchoalveolar lavage (BAL) of infected mice potently suppressed T cell proliferation ex vivo in a dosedependent manner, which provided evidence that they can be defined as G-MDSCs. Intriguingly, the suppressive capability of G-MDSCs isolated from lungs, spleens or bone marrow of P. aeruginosa infected mice was potently enhanced on cellular basis when compared to G-MDSCs isolated from control mice. Contrarily, G-MDSCs isolated from in vitro expanded Cftr-/- splenocytes were less suppressive than G-MDSCs isolated from in vitro expanded wildtype splenocytes, implying a potential role for CFTR on G- MDSC-mediated suppression. Altogether, we could demonstrate, that CFTR deficiency seems to hamper G-MDSCs’ suppressive potential, whereas pulmonary P. aeruginosa airway infection induces G-MDSCs and enhances their suppressive capability, and thereby define a mechanism by which P. aerugionsa undermines host immunity in vivo.
Publications
- Myeloid-Derived Suppressor Cells in Bacterial Infections. Front Cell Infect Microbiol. 2016 Mar 31;6:37
Ost M, Singh A, Peschel A, Mehling R, Rieber N, Hartl D
(See online at https://doi.org/10.3389/fcimb.2016.00037) - Pseudomonas aeruginosa Airway Infection Recruits and Modulates Neutrophilic Myeloid-Derived Suppressor Cells. Front Cell Infect Microbiol. 2016 Nov 29;6:167
Öz HH, Zhou B, Voss P, Carevic M, Schroth C, Frey N, Rieber N, Hector A, Hartl D
(See online at https://doi.org/10.3389/fcimb.2016.00167) - The emerging role of myeloid-derived suppressor cells in lung diseases. Eur Respir J. 2016 Mar;47(3):967-77
Kolahian S, Öz HH, Zhou B, Griessinger CM, Rieber N, Hartl D
(See online at https://doi.org/10.1183/13993003.01572-2015)
