Inflammasome-Mediated Production of IL-1β Is Required for Neutrophil Recruitment against <i>Staphylococcus aureus</i> In Vivo

Miller, Lloyd S.; Pietras, Eric M.; Uricchio, Lawrence H.; Hirano, Kathleen; Rao, Shyam; Lin, Heping; O’Connell, Ryan M.; Iwakura, Yoichiro; Cheung, Ambrose L.; Cheng, Genhong; Modlin, Robert L.

doi:10.4049/jimmunol.179.10.6933

Cited by 301 publications

(215 citation statements)

References 69 publications

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“…infection models. Our data are in general agreement with those from earlier studies showing that IL-1␤ promotes the production of neutrophil ERL CXC chemokines during acute inflammatory arthritis (38)(39)(40) and S. aureus-induced dermatitis (27). All together, the present study identifies a cytokine circuit whereby GBS-induced secretion of IL-1␤ stimulates resident tissue cells to produce ERL CXC chemokines.…”

Section: Discussionsupporting

confidence: 93%

“…We initially found that IL-1␤ is a fundamental, nonredundant factor for host resistance against GBS. These data extend to this pathogen the results of previous work on the importance of IL-1␤ or IL-1R in host defenses against other species of extracellular bacteria, such as Streptococcus pneumoniae and S. aureus (26)(27)(28)(29)(30). Next, we went on to study the mechanisms underlying the effects of IL-1␤ and focused on neutrophilic polymorphonuclear leukocytes for three reasons.…”

Section: Discussionmentioning

confidence: 55%

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The Interleukin-1β/CXCL1/2/Neutrophil Axis Mediates Host Protection against Group B Streptococcal Infection

et al. 2014

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Previous studies have indicated that group B streptococcus (GBS), a frequent human pathogen, potently induces the release of interleukin-1␤ (IL-1␤), an important mediator of inflammatory responses. Since little is known about the role of this cytokine in GBS disease, we analyzed the outcome of infection in IL-1␤-deficient mice. These animals were markedly sensitive to GBS infection, with most of them dying under challenge conditions that caused no deaths in wild-type control mice. Lethality was due to the inability of the IL-1␤-deficient mice to control local GBS replication and dissemination to target organs, such as the brain and the kidneys. Moreover, in a model of inflammation induced by the intraperitoneal injection of killed GBS, a lack of IL-1␤ was associated with selective impairment in the production of the neutrophil chemokines CXCL1 and CXCL2 and in neutrophil recruitment to the peritoneal cavity. Decreased blood neutrophil counts and impaired neutrophil recruitment to the brain and kidneys were also observed during GBS infection in IL-1␤-deficient mice concomitantly with a reduction in CXCL1 and CXCL2 tissue levels. Notably, the hypersusceptibility to GBS infection observed in the immune-deficient animals was recapitulated by neutrophil depletion with anti-Gr1 antibodies. Collectively, our data identify a cytokine circuit that involves IL-1␤-induced production of CXCL1 and CXCL2 and leads the recruitment of neutrophils to GBS infection sites. Moreover, our data point to an essential role of these cells in controlling the progression and outcome of GBS disease.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 55%

The Interleukin-1β/CXCL1/2/Neutrophil Axis Mediates Host Protection against Group B Streptococcal Infection

et al. 2014

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“…In addition, Hla activates the NLRP3 inflammasome in a variety of cells, resulting in the release of the inflammatory cytokine IL-1␤ (67,68,82). Although neutrophils and IL-1␤ are needed for the ultimate clearance of S. aureus SSTI (83,84), limiting inflammation caused by bacterial toxins clearly benefits the host.…”

Section: Discussionmentioning

confidence: 99%

ω-Hydroxyemodin Limits Staphylococcus aureus Quorum Sensing-Mediated Pathogenesis and Inflammation

Daly

Elmore

Kavanaugh

et al. 2015

Antimicrob Agents Chemother

117

147

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d Antibiotic-resistant pathogens are a global health threat. Small molecules that inhibit bacterial virulence have been suggested as alternatives or adjuncts to conventional antibiotics, as they may limit pathogenesis and increase bacterial susceptibility to host killing. Staphylococcus aureus is a major cause of invasive skin and soft tissue infections (SSTIs) in both the hospital and community settings, and it is also becoming increasingly antibiotic resistant. Quorum sensing (QS) mediated by the accessory gene regulator (agr) controls virulence factor production essential for causing SSTIs. We recently identified -hydroxyemodin (OHM), a polyhydroxyanthraquinone isolated from solid-phase cultures of Penicillium restrictum, as a suppressor of QS and a compound sought for the further characterization of the mechanism of action. At concentrations that are nontoxic to eukaryotic cells and subinhibitory to bacterial growth, OHM prevented agr signaling by all four S. aureus agr alleles. OHM inhibited QS by direct binding to AgrA, the response regulator encoded by the agr operon, preventing the interaction of AgrA with the agr P2 promoter. Importantly, OHM was efficacious in a mouse model of S. aureus SSTI. Decreased dermonecrosis with OHM treatment was associated with enhanced bacterial clearance and reductions in inflammatory cytokine transcription and expression at the site of infection. Furthermore, OHM treatment enhanced the immune cell killing of S. aureus in vitro in an agr-dependent manner. These data suggest that bacterial disarmament through the suppression of S. aureus QS may bolster the host innate immune response and limit inflammation.

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“…These include extracellular pathogens, such as Streptococcus pneumoniae, Staphylococcus aureus, and Klebsiella pneumoniae (38)(39)(40), as well as intracellular bacteria, e.g., Listeria monocytogenes and Mycobacterium tuberculosis (41)(42)(43). Many papers describe the interaction of these pathogens with inflammasomes and the subsequent generation of IL-1␤ signals; these are summarized in recent reviews (44,45).…”

Section: Discussionmentioning

confidence: 99%

Distinct Contributions of Interleukin-1α (IL-1α) and IL-1β to Innate Immune Recognition of Pseudomonas aeruginosa in the Lung

Moussawi

Kazmierczak

2014

Infect Immun

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The bacterial pathogen Pseudomonas aeruginosa causes acute infections associated with significant morbidity and mortality. P. aeruginosa elicits strong innate immune responses in immunocompetent hosts, and the resulting recruitment of neutrophils to the site of infection is necessary for bacterial clearance. P. aeruginosa lipopolysaccharide and flagellin are recognized by extracellular Toll-like receptors, but the most rapid responses to infection occur when cytosolic receptors sense flagellin or type 3 secretion system (T3SS) structural proteins. The subsequent activation of the NLRC4 inflammasome and caspase-1 generates an interleukin-1␤ (IL-1␤) signal that is required for the rapid neutrophilic response. A T3SS effector, exotoxin U (ExoU), can inhibit activation of the NLRC4 inflammasome and caspase-1. Thus, our observation that IL-1 receptor (IL-1R)-mediated signals were still required to initiate a response to ExoU-producing bacteria was unexpected. As both IL-1␣ and IL-1␤ signal via the IL-1R, we examined immune responses in mice lacking either of these cytokines. IL-1␤-deficient mice responded to ExoU-producing P. aeruginosa bacteria similarly to wild-type animals; however, IL-1␣-deficient mice had an attenuated immune response. The situation was reversed following infections by ExoU-negative bacteria: here, IL-1␣ was dispensable for neutrophil recruitment, while IL-1␤ was required. IL-1␣ secretion by macrophages infected with ExoU-producing P. aeruginosa isolates was independent of both caspase-1 and caspase-11. This study documents distinct roles for IL-1␣ and IL-1␤ in the response to P. aeruginosa infection as a function of the T3SS effectors produced by the infecting strain. The redundancy of these two cytokines nonetheless allows the infected host to mount a response to ExoU-positive and -negative bacterial isolates.

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Inflammasome-Mediated Production of IL-1β Is Required for Neutrophil Recruitment against Staphylococcus aureus In Vivo

Cited by 301 publications

References 69 publications

The Interleukin-1β/CXCL1/2/Neutrophil Axis Mediates Host Protection against Group B Streptococcal Infection

The Interleukin-1β/CXCL1/2/Neutrophil Axis Mediates Host Protection against Group B Streptococcal Infection

ω-Hydroxyemodin Limits Staphylococcus aureus Quorum Sensing-Mediated Pathogenesis and Inflammation

Distinct Contributions of Interleukin-1α (IL-1α) and IL-1β to Innate Immune Recognition of Pseudomonas aeruginosa in the Lung

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