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

Abstract

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.

NLRP3 Inflammasome Mediates Albumin-induced Renal Tubular Injury through Impaired Mitochondrial Function

“…Cells were pretreated with MnTBAP (100 mM) or CsA (0.5 mg/ml) for 30 min, followed by incubation with albumin (10 mg/ml) for 48 h. Recently, the NLRP3 inflammasome has received increasing attention because of its involvement in the development and progression of various diseases (21,22 (24) demonstrated that the downstream signaling components of the NLRP3 inflammasome, including caspase-1, IL-1␤, and IL-18, were significantly upregulated in the kidneys of proteinuric adults and were correlated with proteinuria severity. However, caspase-1, IL-1␤, and IL-18 expression can also be stimulated via NLPR3-independent pathways (23,25,26). In the present study, we observed that NLRP3 itself was up-regulated in the kidneys of proteinuric children and positively correlated with proteinuria severity.…”

A joint effort: The interplay between the innate and the adaptive immune system in Lyme arthritis

“…Borrelia ‐exposed NOD1‐, NOD2‐, and RICK‐deficient murine cells still produced IL‐6 and TNF‐α. In contrast to previous in vitro data, NLRP3 did not seem to be involved in Lyme arthritis development in a murine model . ASC was pivotal in Lyme arthritis initiation as an important adapter protein in the inflammasome, involved in antigen presentation, lymphocyte migration, NF‐κB activation, and messenger RNA (mRNA) stability and via dedicator of cytokinesis 2 (Dock2) expression and Rac activation .…”

“…Remarkably, B. burgdorferi infection of NOD2 deficiency C57BL/6 mice led to increased inflammation in joints and cardiac tissue when compared to wildtype mice, suggesting that NOD2 tolerization normally protects these mice against dissemination, possibly through the induction of multiple cytokines and interferons . A study by Oosting et al demonstrated that apoptosis‐associated speck‐like protein containing CARD (ASC)/caspase‐1 induction was crucial for IL‐1β production of in murine Lyme arthritis. The activation and secretion of IL‐1β occurred independently from NOD2/RICK, as well as NOD‐like receptor‐family member protein 3 (NLRP3) activation, while the TLR2‐MyD88 pathway was crucial for IL‐1β production.…”

NLRP3 Inflammasome and Host Protection against Bacterial Infection

“…Interestingly, two caspase-1 substrates act together to achieve balanced control of Helicobacter infection and avoid excessive gastric pathology (57). 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).…”