Community-acquired pneumonia is the most common type of pneumonia and remains a leading cause of morbidity and mortality worldwide. Although many different pathogens can contribute to pneumonia, Streptococcus pneumoniae is one of the common bacterial pathogens that underlie community-acquired pneumonia. RIPK3 (receptor-interacting protein kinase 3) is widely recognized as a key modulator of inflammation and cell death. To elucidate a potential role of RIPK3 in pneumonia, we examined plasma from healthy control subjects and patients positive for streptococcal pneumonia. In human studies, RIPK3 protein concentrations were significantly elevated and were identified as a potential plasma marker of pneumococcal pneumonia. To expand these findings, we used an in vivo murine model of pneumococcal pneumonia to demonstrate that RIPK3 deficiency leads to reduced bacterial clearance, severe pathological damage, and high mortality. Our results illustrated that RIPK3 forms a complex with RIPK1, MLKL (mixed-lineage kinase domain-like protein), and MCU (mitochondrial calcium uniporter) to induce mitochondrial calcium uptake and mitochondrial reactive oxygen species(mROS) production during S. pneumoniae infection. In macrophages, RIPK3 initiated necroptosis via the mROS-mediated mitochondrial permeability transition pore opening and NLRP3 inflammasome activation via the mROS-AKT pathway to protect against S. pneumoniae. In conclusion, our study demonstrated a mechanism by which RIPK3-initiated necroptosis is essential for host defense against S. pneumoniae.
Macrophages, Alveolar/immunology , Mitochondria/immunology , Pneumonia, Pneumococcal/immunology , Protein Kinases/immunology , Receptor-Interacting Protein Serine-Threonine Kinases/immunology , Streptococcus pneumoniae/pathogenicity , Aged , Animals , Calcium Channels/genetics , Calcium Channels/immunology , Case-Control Studies , Disease Models, Animal , Female , Gene Expression Regulation , Humans , Inflammasomes/genetics , Inflammasomes/immunology , Macrophages, Alveolar/pathology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Middle Aged , Mitochondria/pathology , Mitochondrial Permeability Transition Pore/immunology , Mitochondrial Permeability Transition Pore/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , NLR Family, Pyrin Domain-Containing 3 Protein/immunology , Necroptosis/genetics , Necroptosis/immunology , Pneumonia, Pneumococcal/complications , Pneumonia, Pneumococcal/microbiology , Protein Kinases/genetics , Proto-Oncogene Proteins c-akt/genetics , Proto-Oncogene Proteins c-akt/immunology , Reactive Oxygen Species/immunology , Reactive Oxygen Species/metabolism , Receptor-Interacting Protein Serine-Threonine Kinases/genetics , Signal Transduction , Streptococcus pneumoniae/immunology
