Abstract
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.
Highlights
Streptococcus pneumoniae (S. pneumoniae) is the most common causative pathogen of community-acquired pneumonia (CAP), an infectious disease which causes 1.2 million deaths per year worldwide [1], despite antibiotics and vaccination
We identified the transcription factor KLF4 in myeloid cells such as phagocytes as potent mediator of the early pro-inflammatory innate immune response and, as potentially interesting target for therapeutic interventions in pneumococcal pneumonia
We previously described that stimulation of macrophages and polymorphonuclear neutrophil (PMN) with S. pneumoniae strongly induced the expression of KLF4 and, thereby, a pro-inflammatory phenotype in both cell types [13, 14]
Summary
Streptococcus pneumoniae (S. pneumoniae) is the most common causative pathogen of community-acquired pneumonia (CAP), an infectious disease which causes 1.2 million deaths per year worldwide [1], despite antibiotics and vaccination. A subset of macrophages, termed tissue-resident macrophages, is probably recruited to the lungs before birth and gradually turns over locally throughout adult life, independently of circulating precursors [7, 10] These cells likely function as local immune sentinels [10]. To further validate KLF4 in phagocytes as potential target for Abbreviations: BAL, bronchoalveolare lavage; BALF, BAL fluid; BM, bone marrow; CAP, community-acquired pneumonia; CFU, colony forming unit; ELISA, Enzyme-linked Immunosorbent Assay; IL, interleukin; KC, keratinocyte chemoattractant; KLF, Krueppel-like factor; PMN, polymorphonuclear neutrophil; MA, murine albumin; mKLF4 KO, myeloid KLF4 knockout; mKLF4 WT, KLF4 wildtype; SOFA, sequential organ failure assessment; S. pneumoniae, Streptococcus pneumoniae; TNF-a, tumor necrosis factor alpha
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