Sir Peter MacCallum Department of Oncology - Research Publications

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Author: ANDREWS, DANIEL × Author: SMYTH, MARK × End date: 2014 × Start date: 2014 × Type: Journal Article ×

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    Type I NKT-cell-mediated TNF-α is a positive regulator of NLRP3 inflammasome priming
    Chow, MT ; Duret, H ; Andrews, DM ; Faveeuw, C ; Moeller, A ; Smyth, MJ ; Paget, C (WILEY, 2014-07)
    The NLRP3 inflammasome plays a crucial role in the innate immune response to pathogens and exogenous or endogenous danger signals. Its activity must be precisely and tightly regulated to generate tailored immune responses. However, the immune cell subsets and cytokines controlling NLRP3 inflammasome activity are still poorly understood. Here, we have shown a link between NKT-cell-mediated TNF-α and NLRP3 inflammasome activity. The NLRP3 inflammasome in APCs was critical to potentiate NKT-cell-mediated immune responses, since C57BL/6 NLRP3 inflammasome-deficient mice exhibited reduced responsiveness to α-galactosylceramide. Importantly, NKT cells were found to act as regulators of NLRP3 inflammasome signaling, as NKT-cell-derived TNF-α was required for optimal IL-1β and IL-18 production by myeloid cells in response to α-galactosylceramide, by acting on the NLRP3 inflammasome priming step. Thus, NKT cells play a role in the positive regulation of NLRP3 inflammasome priming by mediating the production of TNF-α, thus demonstrating another means by which NKT cells control early inflammation.
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    NK cell intrinsic regulation of MIP-1α by granzyme M
    Baschuk, N ; Wang, N ; Watt, SV ; Halse, H ; House, C ; Bird, PI ; Strugnell, R ; Trapani, JA ; Smyth, MJ ; Andrews, DM (NATURE PUBLISHING GROUP, 2014-03)
    Granzymes are generally recognized for their capacity to induce various pathways of perforin-dependent target cell death. Within this serine protease family, Granzyme M (GrzM) is unique owing to its preferential expression in innate effectors such as natural killer (NK) cells. During Listeria monocytogenes infection, we observed markedly reduced secretion of macrophage inflammatory protein-1 alpha (MIP-1α) in livers of GrzM-deficient mice, which resulted in significantly impaired NK cell recruitment. Direct stimulation with IL-12 and IL-15 demonstrated that GrzM was required for maximal secretion of active MIP-1α. This effect was not due to reduced protein induction but resulted from heightened intracellular accumulation of MIP-1α, with reduced release. These results demonstrate that GrzM is a critical mediator of innate immunity that can regulate chemotactic networks and has an important role in the initiation of immune responses and pathogen control.