Dataset Information

NLRX1 protein attenuates inflammatory responses to infection by interfering with the RIG-I-MAVS and TRAF6-NF-?B signaling pathways.

ABSTRACT: The nucleotide-binding domain and leucine-rich-repeat-containing (NLR) proteins regulate innate immunity. Although the positive regulatory impact of NLRs is clear, their inhibitory roles are not well defined. We showed that Nlrx1(-/-) mice exhibited increased expression of antiviral signaling molecules IFN-?, STAT2, OAS1, and IL-6 after influenza virus infection. Consistent with increased inflammation, Nlrx1(-/-) mice exhibited marked morbidity and histopathology. Infection of these mice with an influenza strain that carries a mutated NS-1 protein, which normally prevents IFN induction by interaction with RNA and the intracellular RNA sensor RIG-I, further exacerbated IL-6 and type I IFN signaling. NLRX1 also weakened cytokine responses to the 2009 H1N1 pandemic influenza virus in human cells. Mechanistically, Nlrx1 deletion led to constitutive interaction of MAVS and RIG-I. Additionally, an inhibitory function is identified for NLRX1 during LPS activation of macrophages where the MAVS-RIG-I pathway was not involved. NLRX1 interacts with TRAF6 and inhibits NF-?B activation. Thus, NLRX1 functions as a checkpoint of overzealous inflammation.

SUBMITTER: Allen IC

PROVIDER: S-EPMC3166771 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

NLRX1 protein attenuates inflammatory responses to infection by interfering with the RIG-I-MAVS and TRAF6-NF-κB signaling pathways.

Allen Irving C IC Moore Chris B CB Schneider Monika M Lei Yu Y Davis Beckley K BK Scull Margaret A MA Gris Denis D Roney Kelly E KE Zimmermann Albert G AG Bowzard John B JB Ranjan Priya P Monroe Kathryn M KM Pickles Raymond J RJ Sambhara Suryaprakash S Ting Jenny P Y JP

Immunity 20110601 6

The nucleotide-binding domain and leucine-rich-repeat-containing (NLR) proteins regulate innate immunity. Although the positive regulatory impact of NLRs is clear, their inhibitory roles are not well defined. We showed that Nlrx1(-/-) mice exhibited increased expression of antiviral signaling molecules IFN-β, STAT2, OAS1, and IL-6 after influenza virus infection. Consistent with increased inflammation, Nlrx1(-/-) mice exhibited marked morbidity and histopathology. Infection of these mice with an ...[more]

PMID: 21703540

Similar Datasets

Project description:Background:The development and metastasis of cancer cells are regulated by tumor-associated macrophages (TAMs) present in the surrounding tumor microenvironment. RIG-I is a key pathogen recognition receptor against RNA viruses that regulates innate immunity in cancer progression. Till now, the mechanism of RIG-I regulation of the polarization of TAMs in the progression of hepatocellular carcinoma (HCC) has not been understood. Materials and Methods:Levels of RIG-I and the key proteins in the NF-?B pathway in HCC and paired paracancerous tissues were detected by Western blotting. The transfection efficiency of RIG-I was observed by fluorescence microscopy. The M1 and M2 markers were detected by real-time polymerase chain reaction and FACS assays. Apoptosis of RIG-I lentivirus-infected HCC cells was detected by flow cytometry assay. Death of Hepa1-6 and H22 cells was analyzed by lactate dehydrogenase releasing assay. Results:The level of RIG-I was decreased in HCC tissues as compared to that in the paired paracancerous tissues. Overexpression of RIG-I in mouse peritoneal macrophages increased the expression of the biomarkers CD16/32 and CD11c associated with M1 macrophages. The relative levels of IL-1?, TNF-?, IL-6, and iNOS were significantly increased in RIG-I lentivirus-infected macrophages, whereas the levels of Arg-1 and IL-10 were not significantly different in RIG-I-overexpressed peritoneal macrophages. Moreover, overexpression of RIG-I in peritoneal macrophages promoted apoptosis of Hepa1-6 and H22 cells. Furthermore, overexpression of RIG-I increased the levels of phosphorylated p65 and p-I?B and decreased the level of I?B in peritoneal macrophages. Importantly, the expression of MAVS and TRAF2 was significantly increased in RIG-I lentivirus-infected macrophages. Conclusion:Our results demonstrate that overexpression of RIG-I promoted apoptosis and death of HCC cells. Moreover, RIG-I promoted the polarization of M1 through the RIG-I/MAVS/TRAF2/NF-?B pathway in mice peritoneal macrophages, suggesting that RIG-I may be a novel target in the immunotherapy of HCC.

Project description:Attaching/Effacing (A/E) pathogens including enteropathogenic Escherichia coli (EPEC), enterohemorrhagic E. coli (EHEC) and the rodent equivalent Citrobacter rodentium are important causative agents of foodborne diseases. Upon infection, a myriad of virulence proteins (effectors) encoded by A/E pathogens are injected through their conserved type III secretion systems (T3SS) into host cells where they interfere with cell signaling cascades, in particular the nuclear factor kappaB (NF-?B) signaling pathway that orchestrates both innate and adaptive immune responses for host defense. Among the T3SS-secreted non-LEE-encoded (Nle) effectors, NleC, a metalloprotease, has been recently elucidated to modulate host NF-?B signaling by cleaving NF-?B Rel subunits. However, it remains elusive how NleC recognizes NF-?B Rel subunits and how the NleC-mediated cleavage impacts on host immune responses in infected cells and animals. In this study, we show that NleC specifically targets p65/RelA through an interaction with a unique N-terminal sequence in p65. NleC cleaves p65 in intestinal epithelial cells, albeit a small percentage of the molecule, to generate the p65¹?³? fragment during C. rodentium infection in cultured cells. Moreover, the NleC-mediated p65 cleavage substantially affects the expression of a subset of NF-?B target genes encoding proinflammatory cytokines/chemokines, immune cell infiltration in the colon, and tissue injury in C. rodentium-infected mice. Mechanistically, the NleC cleavage-generated p65¹?³? fragment interferes with the interaction between p65 and ribosomal protein S3 (RPS3), a 'specifier' subunit of NF-?B that confers a subset of proinflammatory gene transcription, which amplifies the effect of cleaving only a small percentage of p65 to modulate NF-?B-mediated gene expression. Thus, our results reveal a novel mechanism for A/E pathogens to specifically block NF-?B signaling and inflammatory responses by cleaving a small percentage of p65 and targeting the p65/RPS3 interaction in host cells, thus providing novel insights into the pathogenic mechanisms of foodborne diseases.

Dataset Information

NLRX1 protein attenuates inflammatory responses to infection by interfering with the RIG-I-MAVS and TRAF6-NF-?B signaling pathways.

Publications

NLRX1 protein attenuates inflammatory responses to infection by interfering with the RIG-I-MAVS and TRAF6-NF-κB signaling pathways.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets