Journal
MICROBIOLOGY SPECTRUM
Volume 10, Issue 2, Pages -Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/spectrum.02049-21
Keywords
IL-6; macrophage; inflammation; pyroptosis; pneumococcal pneumosepsis
Categories
Funding
- National Natural Science Foundation of China [81772153, 31700804]
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This study reveals a novel mechanism for the development of pneumosepsis caused by Streptococcus pneumoniae and the critical protective role of IL-6. IL-6 prevents macrophage death and lung inflammation injury during pneumococcal pneumosepsis. These findings are important for the early identification and treatment of pneumococcal pneumosepsis.
Streptococcus pneumoniae is a leading bacterial cause of a wide range of infections, and pneumococcal pneumosepsis causes high mortality in hosts infected with antibiotic-resistant strains and those who cannot resolve ongoing inflammation. The factors which influence the development and outcome of pneumosepsis are currently unclear. IL-6 is critical for maintaining immune homeostasis, and we determined that this cytokine is also essential for resisting pneumosepsis, as it inhibits macrophage pyroptosis and pyroptosis-related inflammation injury in the lung. IL-6 affected infection outcomes in mice and exerted a protective role, primarily via macrophages. We further found that IL-6 deficiency led to increased lung macrophage death and aggravated lung inflammation, and that exogenous administration of IL-6 protein could decrease macrophage death and alleviate lung tissue inflammation. IL-6 also protected Streptococcus pneumoniae-induced lung macrophage death and lung inflammation injury by inhibiting gasdermin E (GSDME)- and gasdermin D (GSDMD)-mediated pyroptosis. Together, these data reveal a novel mechanism for the development of pneumosepsis and the critical protective role of IL-6. These findings may assist in the early identification and treatment of pneumococcal pneumosepsis. IMPORTANCE Pneumococcal pneumonia has been a significant cause of morbidity and mortality throughout human history. Failing to control pneumococcal pneumonia and resolve ongoing inflammation in a host can cause sepsis, namely pneumococcal pneumosepsis, and death ensues. Few theories have suggested an optimally therapeutic option for this infectious disease. The interleukin-6 (IL-6, a cytokine featuring pleiotropic activity) theory, proposed here, implies that IL-6 acts as a protector against pneumococcal pneumosepsis. IL-6 prevents lung macrophage death and lung inflammation injury by inhibiting a caspase-3-GSDME-mediated switch from apoptosis to pyroptosis and inhibiting caspase-1-GSDMD-mediated classic pyroptosis during pneumococcal pneumosepsis. Thus, IL-6 is an important determinant for controlling bacterial invasion and a homeostatic coordinator of pneumococcal pneumosepsis. This study clarifies a novel mechanism of occurrence and development of pneumonia and secondary sepsis following a Streptococcus pneumoniae infection. It is important for the early identification and treatment of pneumococcal pneumosepsis.
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