Article: Lysis of human neutrophils by community-associated methicillin-resistant Staphylococcus aureus
Authors: Mallary C. Greenlee-Wacker, Silvie Kremserová and William M. Nauseef
Journal: Blood 2017 :blood-2017-02-766253
Key Points:
- Phenotypic features of human neutrophils after ingestion of CA-MRSA contrast with those of phagocytosis-induced apoptosis.
- Human neutrophils fed CA-MRSA lyse by a mechanism dependent in part on active RIPK-3, but independent of TNFα, active RIPK-1, and MLKL
Abstract:
Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) cause infections associated with extensive tissue damage and necrosis. In vitro, human neutrophils fed CA-MRSA lyse by an unknown mechanism that is inhibited by necrostatin-1, an allosteric inhibitor of receptor-interacting serine/threonine kinase 1 (RIPK-1). RIPK-1 figures prominently in necroptosis, a specific form of programmed cell death dependent on RIPK-1, RIPK-3 and the mixed lineage kinase-like protein (MLKL). We previously reported that necrostatin-1 inhibits lysis of human neutrophils fed CA-MRSA and attributed the process to necroptosis. We now extend our studies to examine additional components in the programmed cell death pathway to test the hypothesis that neutrophils fed CA-MRSA undergo necroptosis. Lysis of neutrophils fed CA-MRSA was independent of tumor necrosis factor α, active RIPK-1, and MLKL but dependent on active RIPK-3. Human neutrophils fed CA-MRSA lacked phosphorylated RIPK-1, as well as phosphorylated or oligomerized MLKL. Neutrophils fed CA-MRSA possessed cytoplasmic complexes that included inactive caspase 8, RIPK-1, and RIPK-3 and the composition of the complex remained stable over time. Together these data suggest that neutrophils fed CA-MRSA underwent a novel form of lytic programmed cell death via a mechanism that required RIPK-3 activity but not active RIPK-1 or MLKL and therefore was distinct from necroptosis. Targeting the molecular pathways that culminate in lysis of neutrophils during CA-MRSA infection may serve as novel therapeutic interventions to limit the associated tissue damage.t
Link to journal online: https://doi.org/10.1182/blood-2017-02-766253