Frontline Science: Staphylococcus aureus promotes receptor-interacting protein kinase 3- and protease-dependent production of IL-1? in human neutrophils.

ABSTRACT: Microbial infection elicits robust immune responses that initially depend on polymorphonuclear neutrophils (PMN), which ingest and kill invading bacteria. However, community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) remain viable within PMN and prompt their lysis with concomitant release of damage-associated molecular patterns and proinflammatory cytokines that promote additional inflammation. Here, we show that ultrapure human PMN (>99.8% pure) that have ingested CA-MRSA released interleukin (IL)-1? but not IL-18. The ingested CA-MRSA needed to be viable, and phagocytosis alone was insufficient to stimulate IL-1? secretion from PMN fed CA-MRSA. In contrast to PMN response to the canonical NLRP3 inflammasome agonist nigericin, IL-1? secretion by PMN fed CA-MRSA occurred independently of NLRP3 inflammasome or caspase-1 activation and required instead active receptor-interacting protein kinase 3 (RIPK3) but not RIPK1. Furthermore, inhibition of neutrophil serine proteases blocked pro-IL-1? cleavage in PMN fed CA-MRSA. Taken together, our data suggest that with respect to secretion of IL-1? and IL-18, PMN differ from human macrophages and exhibit agonist-specific responses. After phagocytosis of CA-MRSA, human PMN secreted IL-1? through a previously unrecognized mechanism dependent on RIPK3 and serine proteases but independent of canonical NLRP3 inflammasome and caspase-1 activation.

SUBMITTER: Kremserova S 

PROVIDER: S-EPMC6927048 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature