RIPK3 Activates MLKL-Mediated Necroptosis and Inflammasome Signaling during Streptococcus Infection.

2021 
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 (S. pneumoniae) is one of the common bacterial pathogens that underlie community-acquired pneumonia [1]. Receptor-interacting protein kinase 3 (RIPK3) 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 controls and patients positive with streptococcal pneumonia. In human studies, RIPK3 protein levels 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 and MCU to induce mitochondrial calcium uptake and mitochondrial ROS (mROS) production during S. pneumoniae infection. In macrophages, RIPK3 initiated necroptosis via mROS-mediated mitochondrial permeability transition pore (mPTP) opening and NLRP3 inflammasome activation via 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.
    • Correction
    • Source
    • Cite
    • Save
    • Machine Reading By IdeaReader
    50
    References
    2
    Citations
    NaN
    KQI
    []