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A Common Variant in the Adaptor Mal Regulates Interferon Gamma Signaling. (2016)

Keane, Joseph; O'Sullivan, Mary; O'Neill, Luke; Lavelle, Edward; Corr, Sinead...

A Common Variant in the Adaptor Mal Regulates Interferon Gamma Signaling. (2016)

Keane, Joseph; O'Sullivan, Mary; O'Neill, Luke; Lavelle, Edward; Corr, Sinead; Palsson Mcdermott, Eva; Sheedy, Frederick; Ni Cheallaigh, Cliona

Abstract:

Humans that are heterozygous for the common S180L polymorphism in the Toll-like receptor (TLR) adaptor Mal (encoded by TIRAP) are protected from a number of infectious diseases, including tuberculosis (TB), whereas those homozygous for the allele are at increased risk. The reason for this difference in susceptibility is not clear. We report that Mal has a TLR-independent role in interferon-gamma (IFN-γ) receptor signaling. Mal-dependent IFN-γ receptor (IFNGR) signaling led to mitogen-activated protein kinase (MAPK) p38 phosphorylation and autophagy. IFN-γ signaling via Mal was required for phagosome maturation and killing of intracellular Mycobacterium tuberculosis (Mtb). The S180L polymorphism, and its murine equivalent S200L, reduced the affinity of Mal for the IFNGR, thereby compromising IFNGR signaling in macrophages and impairing responses to TB. Our findings highlight a role for Mal outside the TLR system and imply that genetic variation in TIRAP may be linked to other IFN-γ-r...

http://hdl.handle.net/2262/77444

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Both TLR2 and TRIF contribute to interferon-? production during Listeria infection. (2012)

O'NEILL, LUKE; CORR, SINEAD

Both TLR2 and TRIF contribute to interferon-? production during Listeria infection. (2012)

O'NEILL, LUKE; CORR, SINEAD

Abstract:

Synthesis of interferon-? (IFN-?) is an innate response to cytoplasmic infection with bacterial pathogens. Our recent studies showed that Listeria monocytogenes limits immune detection and IFN-? synthesis via deacetylation of its peptidoglycan, which renders the bacterium resistant to lysozyme degradation. Here, we examined signaling requirements for the massive IFN-? production resulting from the infection of murine macrophages with a mutant strain of L. monocytogenes, ?pgdA, which is unable to modify its peptidoglycan. We report the identification of unconventional signaling pathways to the IFN-? gene, requiring TLR2 and bacterial internalization. Induction of IFN-? was independent of the Mal/TIRAP adaptor protein but required TRIF and the transcription factors IRF3 and IRF7. These pathways were stimulated to a lesser degree by wild-type L. monocytogenes. They operated in both resident and inflammatory macrophages derived from the peritoneal cavity, but not in bone marrow-derived ...

http://hdl.handle.net/2262/66880

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Glutathione Transferase Omega-1 Regulates NLRP3 Inflammasome Activation through NEK7 Deglutathionylation (2019)

Mills, Kingston; Corr, Sinead

Glutathione Transferase Omega-1 Regulates NLRP3 Inflammasome Activation through NEK7 Deglutathionylation (2019)

Mills, Kingston; Corr, Sinead

Abstract:

NLRP3 inflammasome activation contributes to chronic inflammationassociated with autoinflammatorydisease, yet understanding of NLRP3inflammasome regulation is incomplete.Hughes et al. show that thedeglutathionylating enzyme GSTO1-1promotes NLRP3 inflammasomeactivation through deglutathionylation ofNEK7. Furthermore, the GSTO1-1inhibitor C1-27 reduces NLRP3inflammasome activationin vitroandin vivo.

http://hdl.handle.net/2262/90894

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MicroRNA-21 Limits Uptake of Listeria monocytogenes by Macrophages to Reduce the Intracellular Niche and Control Infection. (2017)

CORR, SINEAD; O'NEILL, LUKE

MicroRNA-21 Limits Uptake of Listeria monocytogenes by Macrophages to Reduce the Intracellular Niche and Control Infection. (2017)

CORR, SINEAD; O'NEILL, LUKE

Abstract:

MiRNAs are important post-transcriptional regulators of gene expression. MiRNA expression is a crucial part of host responses to bacterial infection, however there is limited knowledge of their impact on the outcome of infections. We investigated the influence of miR-21 on macrophage responses during infection with Listeria monocytogenes, which establishes an intracellular niche within macrophages. MiR-21 is induced following infection of bone marrow-derived macrophages (BMDMs) with Listeria. MiR-21-/- macrophages display an increased bacterial burden with Listeria at 30 min and 2 h post-infection. This phenotype was reversed by the addition of synthetic miR-21 mimics to the system. To assess the immune response of wildtype (WT) and miR-21-/- macrophages, BMDMs were treated with bacterial LPS or infected with Listeria. There was no difference in IL-10 and IL-6 between WT and miR-21-/- BMDMs in response to LPS or Listeria. TNF-α was increased in miR-21-/- BMDMs stimulated with LPS or...

http://hdl.handle.net/2262/81810

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MyD88 adaptor-like (Mal) functions in the epithelial barrier and contributes to intestinal integrity via protein kinase C (2014)

CORR, SINEAD; O'NEILL, LUKE; PALSSON, EVA; FALLON, PADRAIC

MyD88 adaptor-like (Mal) functions in the epithelial barrier and contributes to intestinal integrity via protein kinase C (2014)

CORR, SINEAD; O'NEILL, LUKE; PALSSON, EVA; FALLON, PADRAIC

Abstract:

The prognosis of epithelial ovarian cancer is poor in part due to the high frequency of chemoresistance. Recent evidence points to the Toll-like receptor-4 (TLR4), and particularly its adaptor protein MyD88, as one potential mediator of this resistance. This study aims to provide further evidence that MyD88 positive cancer cells are clinically significant, stem-like and reproducibly detectable for the purposes of prognostic stratification. Expression of TLR4 and MyD88 was assessed immunohistochemically in 198 paraffin-embedded ovarian tissues and in an embryonal carcinoma model of cancer stemness. In parallel, expression of TLR4 and MyD88 mRNA and regulatory microRNAs (miR-21 and miR-146a) was assessed, as well as in a series of chemosensitive and resistant cancer cells lines. Functional analysis of the pathway was assessed in chemoresistant SKOV-3 ovarian cancer cells. TLR4 and MyD88 expression can be reproducibly assessed via immunohistochemistry using a semi-quantitative scoring ...

http://hdl.handle.net/2262/75436

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MyD88 adaptor-like (Mal) regulates intestinal homeostasis and colitis-associated colorectal cancer in mice. (2014)

FALLON, PADRAIC; CORR, SINEAD

MyD88 adaptor-like (Mal) regulates intestinal homeostasis and colitis-associated colorectal cancer in mice. (2014)

FALLON, PADRAIC; CORR, SINEAD

Abstract:

Toll-like receptors (TLRs) play a central role in the recognition and response to microbial pathogens and in the maintenance and function of the epithelial barrier integrity in the gut. The protein MyD88 adaptor-like (Mal/TIRAP) serves as a bridge between TLR2/TLR4- and MyD88-mediated signaling to orchestrate downstream inflammatory responses. Whereas MyD88 has an essential function in the maintenance of intestinal homeostasis, a role for Mal in this context is less well described. Colitis was induced in wild-type (WT) and Mal-deficient (Mal(-/-)) mice by administration of dextran sodium sulfate (DSS). Colitis-associated cancer was induced by DSS and azoxymethane (AOM) treatment. Chimeric mice were generated by total body gamma irradiation followed by transplantation of bone marrow cells. In the DSS model of colon epithelial injury, Mal(-/-) mice developed increased inflammation and severity of colitis relative to WT mice. Mal(-/-) mice demonstrated the presence of inflammatory cell...

http://hdl.handle.net/2262/75275

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Promyelocytic leukemia protein interacts with the apoptosis-associated speck-like protein to limit inflammasome activation (2014)

O'NEILL, LUKE; QUINN, SUSAN; BOURKE, NOLLAIG; CORR, SINEAD

Promyelocytic leukemia protein interacts with the apoptosis-associated speck-like protein to limit inflammasome activation (2014)

O'NEILL, LUKE; QUINN, SUSAN; BOURKE, NOLLAIG; CORR, SINEAD

Abstract:

The apoptosis-associated speck-like protein containing a caspase-activating recruitment domain (ASC) is an essential component of several inflammasomes, multiprotein complexes that regulate caspase-1 activation and inflammation. We report here an interaction between promyelocytic leukemia protein (PML) and ASC. We observed enhanced formation of ASC dimers in PML-deficient macrophages. These macrophages also display enhanced levels of ASC in the cytosol. Furthermore, IL-1β production was markedly enhanced in these macrophages in response to both NLRP3 and AIM2 inflammasome activation and following bone marrow-derived macrophage infection with herpes simplex virus-1 (HSV-1) and Salmonella typhimurium. Collectively, our data indicate that PML limits ASC function, retaining ASC in the nucleus.

http://hdl.handle.net/2262/75435

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Protective role for caspase-11 during acute experimental murine colitis. (2015)

O'NEILL, LUKE; RAVERDEAU, MATHILDE; MILLS, KINGSTON; CREAGH, EMMA; CORR, SINEAD

Protective role for caspase-11 during acute experimental murine colitis. (2015)

O'NEILL, LUKE; RAVERDEAU, MATHILDE; MILLS, KINGSTON; CREAGH, EMMA; CORR, SINEAD

Abstract:

Activation of the noncanonical inflammasome, mediated by caspase-11, serves as an additional pathway for the production of the proinflammatory cytokines IL-1β and IL-18. Noncanonical inflammasome activity occurs during host defense against Gram-negative bacteria and in models of acute septic shock. We propose that the noncanonical inflammasome is activated in mice during acute intestinal inflammation elicited by dextran sodium sulfate (DSS), a model of experimental colitis. We find that caspase-11−/− mice display enhanced susceptibility to DSS, because of impaired IL-18 production. The impaired IL-18 levels observed are shown to result in reduced intestinal epithelial cell proliferation and increased cell death. We also suggest that a novel type II IFN–dependent, type I IFN-TRIF–independent signaling pathway is required for in vivo caspase-11 production in intestinal epithelial cells during DSS colitis. Collectively, these data suggest that IFN-γ–mediated caspase-11 expression has a...

http://hdl.handle.net/2262/77442

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Succinate is an inflammatory signal that induces IL-1 beta through HIF-1 alpha (2013)

MCGETTRICK-DILLON, ANNE; CORR, SINEAD; PALSSON, EVA; KELLY, VINCENT; O'NEILL, LUKE

Succinate is an inflammatory signal that induces IL-1 beta through HIF-1 alpha (2013)

MCGETTRICK-DILLON, ANNE; CORR, SINEAD; PALSSON, EVA; KELLY, VINCENT; O'NEILL, LUKE

Abstract:

Macrophages activated by the Gram-negative bacterial product lipopolysaccharide switch their core metabolism from oxidative phosphorylation to glycolysis. Here we show that inhibition of glycolysis with 2-deoxyglucose suppresses lipopolysaccharide-induced interleukin-1β but not tumour-necrosis factor-α in mouse macrophages. A comprehensive metabolic map of lipopolysaccharide-activated macrophages shows upregulation of glycolytic and downregulation of mitochondrial genes, which correlates directly with the expression profiles of altered metabolites. Lipopolysaccharide strongly increases the levels of the tricarboxylic-acid cycle intermediate succinate. Glutamine-dependent anerplerosis is the principal source of succinate, although the 'GABA (γ-aminobutyric acid) shunt' pathway also has a role. Lipopolysaccharide-induced succinate stabilizes hypoxia-inducible factor-1α, an effect that is inhibited by 2-deoxyglucose, with interleukin-1β as an important target. Lipopolysacchar...

http://hdl.handle.net/2262/72421