The Caspase 1 Inflammasome Is Not Required for Control of Murine Lyme Borreliosis

Liu, Nengyin; Belperron, Alexia A.; Booth, Carmen J.; Bockenstedt, Linda K.

doi:10.1128/iai.00100-09

Cited by 20 publications

(19 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…While we are unable to formally exclude the possibility of NLRP3 (cryopyrin) or other potential NLRs as potential receptors governing IFN profile induction, the failure of cytosolically administered B. burgdorferi to activate IFN-responsive gene transcription argues against this possibility. In addition, Liu and colleagues recently reported that the inflammasome is not utilized for B. burgdorferi-directed host defense (24). Collectively, our data indicate that B. burgdorferi likely utilizes an (11,14,15,23), induction of IFN-responsive genes by B. burgdorferi-stimulated BMDMs was IRF3 dependent (Fig.…”

Section: Discussionsupporting

confidence: 59%

The Lyme Disease SpirocheteBorrelia burgdorferiUtilizes Multiple Ligands, Including RNA, for Interferon Regulatory Factor 3-Dependent Induction of Type I Interferon-Responsive Genes

Miller

Maylor-Hagen

et al. 2010

Infect Immun

View full text Add to dashboard Cite

We recently discovered a critical role for type I interferon (IFN) in the development of murine Lyme arthritis. Borrelia burgdorferi-mediated induction of IFN-responsive genes by bone marrow-derived macrophages (BMDMs) was dependent upon a functional type I IFN receptor but independent of Toll-like receptor 2 (TLR2), TLR4, TLR9, and the adapter molecule MyD88. We now demonstrate that induction of the IFN transcriptional profile in B. burgdorferi-stimulated BMDMs occurs independently of the adapter TRIF and of the cytoplasmic sensor NOD2. In contrast, B. burgdorferi-induced transcription of these genes was dependent upon a rapid STAT1 feedback amplification pathway. Type I interferons (IFNs) have long been recognized as potent antiviral cytokines and have also been associated with the response to several intracellular bacterial and protozoan pathogens, including Listeria monocytogenes, Francisella tularensis, and Trypanosoma cruzi (15,20,23,47). Recent reports have also linked type I IFN production with host defense to extracellular bacterial pathogens, such as group A and group B streptococci (11,14). Type I IFN production has been implicated in the development of autoimmune diseases, including systemic lupus erythematosus (SLE) and juvenile idiopathic arthritis (JIA), and in arthritis associated with type I IFN treatment of hepatitis C and multiple sclerosis patients (13,28,40,44,52). In addition, we recently uncovered a novel role for type I IFN in the development of subacute murine arthritis caused by the Lyme disease spirochete Borrelia burgdorferi Although TLRs and RLRs utilize different adapter molecules, both pathways culminate in the downstream production of type I IFNs through the activation of the IRF kinases TBK1 and/or IKKε1 and the subsequent phosphorylation of the transcription factors IRF3 and/or IRF7, depending on the cell type and pathogen involved. Type I IFNs can then amplify the production of more type I IFN and IFN-responsive genes through ligation of the type I IFN receptor and the resultant downstream activation of JAK-STAT-mediated signal transduction events (21,45).

show abstract

Section: Discussionsupporting

confidence: 59%

The Lyme Disease SpirocheteBorrelia burgdorferiUtilizes Multiple Ligands, Including RNA, for Interferon Regulatory Factor 3-Dependent Induction of Type I Interferon-Responsive Genes

Miller

Maylor-Hagen

et al. 2010

Infect Immun

View full text Add to dashboard Cite

show abstract

“…However, at later time points after Borrelia exposure, caspase-1 might play a different role. Liu et al ., [32] showed that caspase-1 KO mice display higher arthritis scores at day 14 postinfection. On day 45, the arthritis scores in these mice are lower as compared to WT-type mice.…”

Section: Discussionmentioning

confidence: 99%

Murine Borrelia arthritis is highly dependent on ASC and caspase-1, but independent of NLRP3

et al. 2012

View full text Add to dashboard Cite

IntroductionThe protein platform called the NOD-like-receptor -family member (NLRP)-3 inflammasome needs to be activated to process intracellular caspase-1. Active caspase-1 is able to cleave pro-Interleukin (IL)-1β, resulting in bioactive IL-1β. IL-1β is a potent proinflammatory cytokine, and thought to play a key role in the pathogenesis of Lyme arthritis, a common manifestation of Borrelia burgdorferi infection. The precise pathways through which B. burgdorferi recognition leads to inflammasome activation and processing of IL-1β in Lyme arthritis has not been elucidated. In the present study, we investigated the contribution of several pattern recognition receptors and inflammasome components in a novel murine model of Lyme arthritis.MethodsLyme arthritis was elicited by live B. burgdorferi, injected intra-articularly in knee joints of mice. To identify the relevant pathway components, the model was applied to wild-type, NLRP3-/-, ASC-/-, caspase-1-/-, NOD1-/-, NOD2-/-, and RICK-/- mice. As a control, TLR2-/-, Myd88-/- and IL-1R-/- mice were used. Peritoneal macrophages and bone marrow-derived macrophages were used for in vitro cytokine production and inflammasome activation studies. Joint inflammation was analyzed in synovial specimens and whole knee joints. Mann-Whitney U tests were used to detect statistical differences.ResultsWe demonstrate that ASC/caspase-1-driven IL-1β is crucial for induction of B. burgdorferi-induced murine Lyme arthritis. In addition, we show that B. burgdorferi-induced murine Lyme arthritis is less dependent on NOD1/NOD2/RICK pathways while the TLR2-MyD88 pathway is crucial.ConclusionsMurine Lyme arthritis is strongly dependent on IL-1 production, and B. burgdorferi induces inflammasome-mediated caspase-1 activation. Next to that, murine Lyme arthritis is ASC- and caspase-1-dependent, but NLRP3, NOD1, NOD2, and RICK independent. Also, caspase-1 activation by B. burgdorferi is dependent on TLR2 and MyD88. Based on present results indicating that IL-1 is one of the major mediators in Lyme arthritis, there is a rationale to propose that neutralizing IL-1 activity may also have beneficial effects in chronic Lyme arthritis.

show abstract

“…The gram-negative spirochete, Borrelia burgdorferi , a pathogen of chronic Lyme disease-associated arthritis, activates the inflammasome in a manner dependent on ASC and caspase-1, but not NLRP3 (58, 59). In addition, IL-1 is a major pathogenic mediator of Lyme arthritis and is not required for control of Lyme borreliosis in murine models (59, 60). …”

Section: The Pathogenic Roles Of Nlrp3 Inflammasome Activation In Bacmentioning

confidence: 99%

NLRP3 Inflammasome and Host Protection against Bacterial Infection

Kim

2013

J Korean Med Sci

View full text Add to dashboard Cite

The inflammasome is a multi-protein complex that induces maturation of inflammatory cytokines interleukin (IL)-1β and IL-18 through activation of caspase-1. Several nucleotide binding oligomerization domain-like receptor family members, including NLRP3, recognize unique microbial and danger components and play a central role in inflammasome activation. The NLRP3 inflammasome is critical for maintenance of homeostasis against pathogenic infections. However, inflammasome activation acts as a double-edged sword for various bacterial infections. When the IL-1 family of cytokines is secreted excessively, they cause tissue damage and extensive inflammatory responses that are potentially hazardous for the host. Emerging evidence has shown that diverse bacterial pathogens or their components negatively regulate inflammasome activation to escape the immune response. In this review, we discuss the current knowledge of the roles and regulation of the NLRP3 inflammasome during bacterial infections. Activation and regulation of the NLRP3 inflammasome should be tightly controlled to prevent virulence and pathology during infections. Understanding the roles and regulatory mechanisms of the NLRP3 inflammasome is essential for developing potential treatment approaches against pathogenic infections.

show abstract

The Caspase 1 Inflammasome Is Not Required for Control of Murine Lyme Borreliosis

Cited by 20 publications

References 46 publications

The Lyme Disease SpirocheteBorrelia burgdorferiUtilizes Multiple Ligands, Including RNA, for Interferon Regulatory Factor 3-Dependent Induction of Type I Interferon-Responsive Genes

The Lyme Disease SpirocheteBorrelia burgdorferiUtilizes Multiple Ligands, Including RNA, for Interferon Regulatory Factor 3-Dependent Induction of Type I Interferon-Responsive Genes

Murine Borrelia arthritis is highly dependent on ASC and caspase-1, but independent of NLRP3

NLRP3 Inflammasome and Host Protection against Bacterial Infection

Contact Info

Product

Resources

About