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Browsing by Author "TeKippe, Erin McElvania"

Now showing 1 - 4 of 4
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    Characterization of NLRP12 during the In Vivo Host Immune Response to Klebsiella pneumoniae and Mycobacterium tuberculosis
    Allen, Irving C.; TeKippe, Erin McElvania; Wilson, Justin E.; Lich, John D.; Arthur, Janelle C.; Sullivan, Jonathan T.; Braunstein, Miriam; Ting, Jenny P.-Y. (PLOS, 2013-04-05)
    The majority of nucleotide binding domain leucine rich repeats-containing (NLR) family members has yet to be functionally characterized. Of the described NLRs, most are considered to be proinflammatory and facilitate IL-1β production. However, a newly defined sub-group of NLRs that function as negative regulators of inflammation have been identified based on their abilities to attenuate NF-κB signaling. NLRP12 (Monarch-1) is a prototypical member of this sub-group that negatively regulates both canonical and noncanonical NF-κB signaling in biochemical assays and in colitis and colon cancer models. The role of NLRP12 in infectious diseases has not been extensively studied. Here, we characterized the innate immune response of Nlrp12−/− mice following airway exposure to LPS, Klebsiella pneumoniae and Mycobacterium tuberculosis. In response to E. coli LPS, Nlrp12−/− mice showed a slight decrease in IL-1β and increase in IL-6 production, but these levels were not statistically significant. During K. pneumoniae infection, we observed subtle differences in cytokine levels and significantly reduced numbers of monocytes and lymphocytes in Nlrp12−/− mice. However, the physiological relevance of these findings is unclear as no overt differences in the development of lung disease were observed in the Nlrp12−/− mice. Likewise, Nlrp12−/− mice demonstrated pathologies similar to those observed in the wild type mice following M. tuberculosis infection. Together, these data suggest that NLRP12 does not significantly contribute to the in vivo host innate immune response to LPS stimulation, Klebsiella pneumonia infection or Mycobacterium tuberculosis.
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    Granuloma Formation and Host Defense in Chronic Mycobacterium tuberculosis Infection Requires PYCARD/ASC but Not NLRP3 or Caspase-1
    TeKippe, Erin McElvania; Allen, Irving C.; Hulseberg, Paul D.; Sullivan, Jonathan T.; McCann, Jessica R.; Sandor, Matys; Braunstein, Miriam; Ting, Jenny P.-Y. (PLOS, 2010-08-20)
    The NLR gene family mediates host immunity to various acute pathogenic stimuli, but its role in chronic infection is not known. This paper addressed the role of NLRP3 (NALP3), its adaptor protein PYCARD (ASC), and caspase-1 during infection with Mycobacterium tuberculosis (Mtb). Mtb infection of macrophages in culture induced IL-1b secretion, and this requires the inflammasome components PYCARD, caspase-1, and NLRP3. However, in vivo Mtb aerosol infection of Nlrp32/2, Casp-12/2, and WT mice showed no differences in pulmonary IL-1b production, bacterial burden, or long-term survival. In contrast, a significant role was observed for Pycard in host protection during chronic Mtb infection, as shown by an abrupt decrease in survival of Pycard2/2 mice. Decreased survival of Pycard2/2 animals was associated with defective granuloma formation. These data demonstrate that PYCARD exerts a novel inflammasome-independent role during chronic Mtb infection by containing the bacteria in granulomas.
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    The NLRP3 inflammasome functions as a negative regulator of tumorigenesis during colitis-associated cancer
    Allen, Irving C.; TeKippe, Erin McElvania; Woodford, Rita-Marie T.; Uronis, Joshua M.; Holl, Eda K.; Rogers, Arlin B.; Herfarth, Hans H.; Jobin, Christian; Ting, Jenny P.-Y. (Rockefeller University Press, 2010-05-10)
    Colitis-associated cancer (CAC) is a major complication of inflammatory bowel diseases. We show that components of the inflammasome are protective during acute and recurring colitis and CAC in the dextran sulfate sodium (DSS) and azoxymethane + DSS models. Mice lacking the inflammasome adaptor protein PYCARD (ASC) and caspase-1 demonstrate increased disease outcome, morbidity, histopathology, and polyp formation. The increased tumor burden is correlated with attenuated levels of IL-1Β and IL-18 at the tumor site. To decipher the nucleotide-binding domain, leucine-rich-repeat-containing (NLR) component that is involved in colitis and CAC, we assessed Nlrp3 and Nlrc4 deficient mice. Nlrp3-l- mice showed an increase in acute and recurring colitis and CAC, although the disease outcome was less severe in Nlrp3-l- mice than in Pycard-l- or Casp1-l- animals. No significant differences were observed in disease progression or outcome in Nlrc4-l- mice compared with similarly treated wild-type animals. Bone marrow reconstitution experiments show that Nlrp3 gene expression and function in hematopoietic cells, rather than intestinal epithelial cells or stromal cells, is responsible for protection against increased tumorigenesis. These data suggest that the inflammasome functions as an attenuator of colitis and CAC.
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    Staphylococcus aureus alpha-Hemolysin Activates the NLRP3-Inflammasome in Human and Mouse Monocytic Cells
    Craven, Robin R.; Gao, Xi; Allen, Irving C.; Gris, Denis; Wardenburg, Juliane Bubeck; TeKippe, Erin McElvania; Ting, Jenny P.-Y.; Duncan, Joseph A. (PLOS, 2009-10-14)
    Community Acquired Methicillin Resistant Staphylococcus aureus (CA-MRSA) causes severe necrotizing infections of the skin, soft tissues, and lungs. Staphylococcal a-hemolysin is an essential virulence factor in mouse models of CA-MRSA necrotizing pneumonia. S. aureus a-hemolysin has long been known to induce inflammatory signaling and cell death in host organisms, however the mechanism underlying these signaling events were not well understood. Using highly purified recombinant ahemolysin, we now demonstrate that a-hemolysin activates the Nucleotide-binding domain and leucine-rich repeat containing gene family, pyrin domain containing 3 protein (NLRP3)-inflammasome, a host inflammatory signaling complex involved in responses to pathogens and endogenous danger signals. Non-cytolytic mutant a-hemolysin molecules fail to elicit NLRP3-inflammasome signaling, demonstrating that the responses are not due to non-specific activation of this innate immune signaling system by bacterially derived proteins. In monocyte-derived cells from humans and mice, inflammasome assembly in response to a-hemolysin results in activation of the cysteine proteinase, caspase-1. We also show that inflammasome activation by a-hemolysin works in conjunction with signaling by other CA-MRSA-derived Pathogen Associated Molecular Patterns (PAMPs) to induce secretion of pro-inflammatory cytokines IL-1b and IL-18. Additionally, ahemolysin induces cell death in these cells through an NLRP3-dependent program of cellular necrosis, resulting in the release of endogenous pro-inflammatory molecules, like the chromatin-associated protein, High-mobility group box 1 (HMGB1). These studies link the activity of a major S. aureus virulence factor to a specific host signaling pathway. The cellular events linked to inflammasome activity have clear relevance to the disease processes associated with CA-MRSA including tissue necrosis and inflammation.