TY - JOUR
T1 - Krueppel-Like Factor 4 Expression in Phagocytes Regulates Early Inflammatory Response and Disease Severity in Pneumococcal Pneumonia
AU - Herta, Toni
AU - Bhattacharyya, Aritra
AU - Rosolowski, Maciej
AU - Conrad, Claudia
AU - Gurtner, Corinne
AU - Gruber, Achim D.
AU - Ahnert, Peter
AU - Gutbier, Birgitt
AU - Frey, Doris
AU - Suttorp, Norbert
AU - Hippenstiel, Stefan
AU - Zahlten, Janine
N1 - Funding Information: This work was supported by DFG SFB-TR84 grants to JZ, SH, AG, and NS (projects C2, B1, Z1b and B6), Jürgen Manchot Stiftung to TH and AB and the German Federal Ministry of Education and Research (BMBF) within the framework of the e:Med research and funding concept (project SYMAPATH, grant number 01ZX1906B) and the German Center fur Lung Research (PROGRESS, grant numbers 82DZU19A2 und 82DZLJ19B2), MR, PA, and NS. Publisher Copyright: © Copyright © 2021 Herta, Bhattacharyya, Rosolowski, Conrad, Gurtner, Gruber, Ahnert, Gutbier, Frey, Suttorp, Hippenstiel and Zahlten.
PY - 2021/9/13
Y1 - 2021/9/13
N2 - The transcription factor Krueppel-like factor (KLF) 4 fosters the pro-inflammatory immune response in macrophages and polymorphonuclear neutrophils (PMNs) when stimulated with Streptococcus pneumoniae, the main causative pathogen of community-acquired pneumonia (CAP). Here, we investigated the impact of KLF4 expression in myeloid cells such as macrophages and PMNs on inflammatory response and disease severity in a pneumococcal pneumonia mouse model and in patients admitted to hospital with CAP. We found that mice with a myeloid-specific knockout of KLF4 mount an insufficient early immune response with reduced levels of pro-inflammatory cytokines and increased levels of the anti-inflammatory cytokine interleukin (IL) 10 in bronchoalveolar lavage fluid and plasma and an impaired bacterial clearance from the lungs 24 hours after infection with S. pneumoniae. This results in higher rates of bacteremia, increased lung tissue damage, more severe symptoms of infection and reduced survival. Higher KLF4 gene expression levels in the peripheral blood of patients with CAP at hospital admission correlate with a favourable clinical presentation (lower sequential organ failure assessment (SOFA) score), lower serum levels of IL-10 at admission, shorter hospital stay and lower mortality or requirement of intensive care unit treatment within 28 days after admission. Thus, KLF4 in myeloid cells such as macrophages and PMNs is an important regulator of the early pro-inflammatory immune response and, therefore, a potentially interesting target for therapeutic interventions in pneumococcal pneumonia.
AB - The transcription factor Krueppel-like factor (KLF) 4 fosters the pro-inflammatory immune response in macrophages and polymorphonuclear neutrophils (PMNs) when stimulated with Streptococcus pneumoniae, the main causative pathogen of community-acquired pneumonia (CAP). Here, we investigated the impact of KLF4 expression in myeloid cells such as macrophages and PMNs on inflammatory response and disease severity in a pneumococcal pneumonia mouse model and in patients admitted to hospital with CAP. We found that mice with a myeloid-specific knockout of KLF4 mount an insufficient early immune response with reduced levels of pro-inflammatory cytokines and increased levels of the anti-inflammatory cytokine interleukin (IL) 10 in bronchoalveolar lavage fluid and plasma and an impaired bacterial clearance from the lungs 24 hours after infection with S. pneumoniae. This results in higher rates of bacteremia, increased lung tissue damage, more severe symptoms of infection and reduced survival. Higher KLF4 gene expression levels in the peripheral blood of patients with CAP at hospital admission correlate with a favourable clinical presentation (lower sequential organ failure assessment (SOFA) score), lower serum levels of IL-10 at admission, shorter hospital stay and lower mortality or requirement of intensive care unit treatment within 28 days after admission. Thus, KLF4 in myeloid cells such as macrophages and PMNs is an important regulator of the early pro-inflammatory immune response and, therefore, a potentially interesting target for therapeutic interventions in pneumococcal pneumonia.
KW - Krueppel-like factor 4
KW - Streptococcus pneumoniae
KW - community-acquired pneumonia
KW - innate immunity
KW - myeloid cells
UR - http://www.scopus.com/inward/record.url?scp=85116061196&partnerID=8YFLogxK
U2 - https://doi.org/10.3389/fimmu.2021.726135
DO - https://doi.org/10.3389/fimmu.2021.726135
M3 - Article
C2 - 34589087
SN - 1664-3224
VL - 12
JO - Frontiers in immunology
JF - Frontiers in immunology
M1 - 726135
ER -