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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

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

Kremserova Silvie S Nauseef William M WM

Journal of leukocyte biology 20181213 3

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 ...[more]

PMID: 30548986

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Project description:BackgroundTreatment of brain tumors, epilepsy, or hemodynamic abnormalities requires a craniotomy to access the brain. Nearly 1 million craniotomies are performed in the US annually, which increase to ~ 14 million worldwide and despite prophylaxis, infectious complications after craniotomy range from 1 to 3%. Approximately half are caused by Staphylococcus aureus (S. aureus), which forms a biofilm on the bone flap that is recalcitrant to antibiotics and immune-mediated clearance. However, the mechanisms responsible for the persistence of craniotomy infection remain largely unknown. The current study examined the role of IL-10 in promoting bacterial survival.MethodsA mouse model of S. aureus craniotomy infection was used with wild type (WT), IL-10 knockout (KO), and IL-10 conditional KO mice where IL-10 was absent in microglia and monocytes/macrophages (CX3CR1CreIL-10 fl/fl) or neutrophils and granulocytic myeloid-derived suppressor cells (G-MDSCs; Mrp8CreIL-10 fl/fl), the major immune cell populations in the infected brain vs. subcutaneous galea, respectively. Mice were examined at various intervals post-infection to quantify bacterial burden, leukocyte recruitment, and inflammatory mediator production in the brain and galea to assess the role of IL-10 in craniotomy persistence. In addition, the role of G-MDSC-derived IL-10 on neutrophil activity was examined.ResultsGranulocytes (neutrophils and G-MDSCs) were the major producers of IL-10 during craniotomy infection. Bacterial burden was significantly reduced in IL-10 KO mice in the brain and galea at day 14 post-infection compared to WT animals, concomitant with increased CD4+ and γδ T cell recruitment and cytokine/chemokine production, indicative of a heightened proinflammatory response. S. aureus burden was reduced in Mrp8CreIL-10 fl/fl but not CX3CR1CreIL-10 fl/fl mice that was reversed following treatment with exogenous IL-10, suggesting that granulocyte-derived IL-10 was important for promoting S. aureus craniotomy infection. This was likely due, in part, to IL-10 production by G-MDSCs that inhibited neutrophil bactericidal activity and TNF production.ConclusionCollectively, these findings reveal a novel role for granulocyte-derived IL-10 in suppressing S. aureus clearance during craniotomy infection, which is one mechanism to account for biofilm persistence.

Dataset Information

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

Publications

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

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