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Staphylococcus aureus activation of NLRP3 inflammasome and necroptosis through MLKL exacerbates pneumonia
Author(s) -
Kitur Kipyegon,
Prince Alice
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.148.5
Subject(s) - necroptosis , inflammasome , immune system , proinflammatory cytokine , microbiology and biotechnology , pathogenesis , staphylococcus aureus , immunology , cytokine , chemistry , programmed cell death , inflammation , biology , apoptosis , bacteria , biochemistry , genetics
Staphylococcus aureus (SA) cause a highly inflammatory pneumonia associated with substantial pulmonary damage. We demonstrate that alveolar macrophages along with other immune effectors are depleted by SA toxin production that activates RIP1/RIP3/MLKL‐mediated necroptosis. SA infected Rip3 ‐/‐ mice and necrostatin‐1s‐treated mice retained significantly greater numbers of immune cells in the airways compared to control mice (p=0.0263 and p=0.0007 respectively). Rip3 ‐/‐ macrophages had increased expression of the anti‐inflammatory markers CD206 (p=0.0104) and CD200R (p=0.0082) and decreased proinflammatory cytokine expression particularly Il‐1β production. These phenotypes were correlated with increased SA clearance and decreased pathology after SA infection. SA pore forming toxins were sufficient to activate necroptosis and NLRP3 inflammasome. MLKL blockade with necrosulfonamide decreased inflammasome activation and production of reactive oxygen species (ROS) induced by SA toxins. However, inhibition of ROS or inflammasome components did not protect immune cells from death. Our findings suggest that the activation of RIP1/RIP3/MLKL‐mediated necroptosis by SA modulates inflammasome activation and leads to loss of key airway immune cells contributing to the pathogenesis of SA pneumonia. Preventing the loss of these cells through necroptosis is a potential therapeutic target to block inflammatory airway damage during SA pneumonia.