Caspase-11 Activation in Response to Bacterial Secretion Systems That Access the Host Cytosol

Inflammasome activation is important for antimicrobial defense because it induces cell death and regulates the secretion of IL-1 family cytokines, which play a critical role in inflammatory responses. The inflammasome activates caspase-1 to process and secrete IL-1β. However, the mechanisms governing IL-1α release are less clear. Recently, a non-canonical inflammasome was described that activates caspase-11 and mediates pyroptosis and release of IL-1α and IL-1β. Caspase-11 activation in response to Gram-negative bacteria requires Toll-like receptor 4 (TLR4) and TIR-domain-containing adaptor-inducing interferon-β (TRIF)-dependent interferon production. Whether additional bacterial signals trigger caspase-11 activation is unknown. Many bacterial pathogens use specialized secretion systems to translocate effector proteins into the cytosol of host cells. These secretion systems can also deliver flagellin into the cytosol, which triggers caspase-1 activation and pyroptosis. However, even in the absence of flagellin, these secretion systems induce inflammasome activation and the release of IL-1α and IL-1β, but the inflammasome pathways that mediate this response are unclear. We observe rapid IL-1α and IL-1β release and cell death in response to the type IV or type III secretion systems of Legionella pneumophila and Yersinia pseudotuberculosis. Unlike IL-1β, IL-1α secretion does not require caspase-1. Instead, caspase-11 activation is required for both IL-1α secretion and cell death in response to the activity of these secretion systems. Interestingly, whereas caspase-11 promotes IL-1β release in response to the type IV secretion system through the NLRP3/ASC inflammasome, caspase-11-dependent release of IL-1α is independent of both the NAIP5/NLRC4 and NLRP3/ASC inflammasomes as well as TRIF and type I interferon signaling. Furthermore, we find both overlapping and non-redundant roles for IL-1α and IL-1β in mediating neutrophil recruitment and bacterial clearance in response to pulmonary infection by L. pneumophila. Our findings demonstrate that virulent, but not avirulent, bacteria trigger a rapid caspase-11-dependent innate immune response important for host defense

Gastric xanthomatosis and cholestasis

We report two cases of gastric xanthomatosis which developed in patients with marked cholestasis. In both cases, one with acute and one with chronic cholestasis, the gastric xanthomas disappeared with resolution of the cholestasis. A review of the literature is also provided.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44402/1/10620_2005_Article_BF01303212.pd

Caspase-11 activation is independent of ASC and NLRC4.

<p>(<b>A</b>) Unprimed B6, <i>Casp1^−/−Casp11^−/−</i>, or <i>Asc^−/−Nlrc4^−/−</i> BMDMs were infected with WT <i>L. pneumophila</i> (WT Lp), Δ<i>dotA</i> Lp, Δ<i>flaA</i> Lp, or PBS (mock infection) for 20 hours, and levels of IL-1α and IL-1β in the supernatants were measured by ELISA. Graphs show the mean ± SEM of triplicate wells. (<b>B</b>) Unprimed B6, <i>Casp1^−/−Casp11^−/−</i>, or <i>Asc^−/−Nlrc4^−/−</i> BMDMs were infected with WT Lp, Δ<i>dotA</i> Lp, Δ<i>flaA</i> Lp, or PBS (mock infection) for 20 hours or treated with LPS+ATP for 1 hour. Levels of processed caspase-1 (casp-1 p10) and caspase-11 (casp-11 p26) in the supernatants, and pro-caspase-1, pro-caspase-11, and β-actin (loading control) in the cell lysates were determined by immunoblot analysis. (<b>C</b>) 8–12 week old B6 and <i>Asc^−/−</i> mice were infected intranasally with either 1×10⁶ Δ<i>flaA</i> Lp or PBS. Bronchoalveolar lavage fluid (BALF) was collected 24 hours post-infection, and levels of IL-1α and IL-1β were measured by ELISA. Graphs show the mean ± SEM of 9 mice per group. Dashed line represents the limit of detection. Data are representative of three independent experiments (A,B) or are displayed as the pooled results of two independent experiments (C). *** is p<0.001 by two-way ANOVA with Bonferroni post-test. ** is p<0.01 by unpaired t-test. NS is not significant.</p