<i>PanR1</i>, a Dominant Negative Missense Allele of the Gene Encoding TNF-α (<i>Tnf</i>), Does Not Impair Lymphoid Development

Rutschmann, Sophie; Hoebe, Kasper; Zalevsky, Jonathan; Du, Xin; Mann, Navjiwan; Dahiyat, Bassil I.; Steed, Paul M.; Beutler, Bruce

doi:10.4049/jimmunol.176.12.7525

Cited by 17 publications

(13 citation statements)

References 56 publications

(40 reference statements)

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“…For in vivo challenge with L. monocytogenes (strain 10403S; Xenogen), 10 5 , 5 ϫ 10 5 , or 10 6 cfu of bioluminescent bacteria were prepared and injected intravenously as described in ref. 35. TNF␣ production by thioglycolate-elicited peritoneal macrophages was measured by L929 bioassay after stimulation with TLR-activating ligands for 4 h as described in ref.…”

Section: And L Monocytogenes Infections and Measurement Of Macrmentioning

confidence: 99%

“…TNF␣ production by thioglycolate-elicited peritoneal macrophages was measured by L929 bioassay after stimulation with TLR-activating ligands for 4 h as described in ref. 35. Pro-IL-1␤, MAPK phosphorylation, and MAPK proteins were measured in lysates derived from 4 ϫ 10 6 bone marrow-derived macrophages grown by using L-929 cell conditioned medium and stimulated with 10 ng/ml LPS (Alexis).…”

Section: And L Monocytogenes Infections and Measurement Of Macrmentioning

confidence: 99%

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Inflammation and autoimmunity caused by a SHP1 mutation depend on IL-1, MyD88, and a microbial trigger

Croker

Lawson

Berger

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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104

127

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A recessive phenotype called spin (spontaneous inflammation) was induced by N -ethyl- N -nitrosourea (ENU) mutagenesis in C57BL/6J mice. Homozygotes display chronic inflammatory lesions affecting the feet, salivary glands and lungs, and antichromatin antibodies. They are immunocompetent and show enhanced resistance to infection by Listeria monocytogenes . TLR-induced TNF and IL-1 production are normal in macrophages derived from spin mice. The autoinflammatory phenotype of spin mice is fully suppressed by compound homozygosity for Myd88 poc , Irak4 otiose , and Il1r1 -null mutations, but not Ticam1 Lps2 , Stat1 m1Btlr , or Tnf -null mutations. Both autoimmune and autoinflammatory phenotypes are suppressed when spin homozygotes are derived into a germ-free environment. The spin phenotype was ascribed to a viable hypomorphic allele of Ptpn6 , which encodes the tyrosine phosphatase SHP1, mutated in mice with the classical motheaten alleles me and me-v . Inflammation and autoimmunity caused by SHP1 deficiency are thus conditional. The SHP1-deficient phenotype is driven by microbes, which activate TLR signaling pathways to elicit IL-1 production. IL-1 signaling via MyD88 elicits inflammatory disease.

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Section: And L Monocytogenes Infections and Measurement Of Macrmentioning

confidence: 99%

Section: And L Monocytogenes Infections and Measurement Of Macrmentioning

confidence: 99%

Inflammation and autoimmunity caused by a SHP1 mutation depend on IL-1, MyD88, and a microbial trigger

Croker

Lawson

Berger

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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104

127

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“…7 This screen has revealed mutant alleles throughout the pathway, from TLRs and the proteins that control their expression, 8 to TNF␣ itself. 9 Here we describe a new mutation affecting TLR-induced TNF␣ secretion that did not affect secretion of IL-6. The causative mutation lay in the gene encoding iRhom2, a catalytically inactive member of the rhomboid protease family.…”

Section: Introductionmentioning

confidence: 91%

iRhom2 is required for the secretion of mouse TNFα

Siggs

Xiao

Wang

et al. 2012

Blood

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107

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TNF␣ is a powerful inflammatory stimulus, central both to the control of infection, and as an agent of inflammatory disease. The most potent inducers of TNF␣ secretion signal through the Toll-like receptors, and we describe here a chemically-induced mutation that impairs this response in macrophages. A missense mutation was revealed in the gene encoding the inactive rhomboid protease iRhom2, which was not complemented by a null allele of the same gene. Neither the missense nor the null allele affected TLR-induced secretion of IL-6. Moreover, unlike a mutation in TNF␣, the iRhom2 missense mutation did not cause enhanced susceptibility to colitis induced by dextran sodium sulfate. These results establish a specific role for iRhom2 in the secretion of TNF␣, and present a new target for the modulation of inflammation. (Blood. 2012; 119(24):5769-5771) IntroductionTLR activation triggers a signaling pathway that culminates in the activation of NF-B and the synthesis of proinflammatory cytokines such as TNF␣. TNF␣, which is synthesized as a membranebound precursor, is liberated from the cell surface by the TNF␣ converting enzyme (TACE, also known as ADAM17). 1,2 Mammalian TACE is also required for the cleavage of other membranebound ligands, including the EGFR ligand TGF␣, 3 whose counterpart in Drosophila is cleaved by the unrelated protease rhomboid-1. 4,5 The rhomboid protease family is also present in mammals, and includes members with no predicted catalytic function, known as iRhoms. 6 Until very recently, the physiologic function of these proteins was unknown.To reveal new regulators of TLR-induced TNF␣, we have stimulated peritoneal macrophages from the progeny of chemicallymutagenized mice. 7 This screen has revealed mutant alleles throughout the pathway, from TLRs and the proteins that control their expression, 8 to TNF␣ itself. 9 Here we describe a new mutation affecting TLR-induced TNF␣ secretion that did not affect secretion of IL-6. The causative mutation lay in the gene encoding iRhom2, a catalytically inactive member of the rhomboid protease family. Methods Mice and positional cloningRhbdf2 sinecure was generated on a C57BL/6J background by N-ethyl-N-nitrosourea mutagenesis as previously described. 10 The index sinecure mutant (C57BL/6J, male) was outcrossed to C57BL/10J females (The Jackson Laboratory) for mapping, and F1 daughters were backcrossed to their father. Mice were grouped into mutant and wild-type cohorts (20 and 15 mice, respectively) based on TNF␣ secretion in response to MALP-2. Individual mice were typed at 70 polymorphic markers across the genome, and genotype frequencies were used to calculate LOD scores at each position. Rhbdf2 amplicons from wild-type and sinecure genomic DNA were sequenced using an ABI 3730xl capillary sequencer. C57BL/6J mice used for mutagenesis were obtained from The Jackson Laboratory. All other mice were obtained from the TSRI breeding colony. Ticam1 Lps2 and Irak2 otiose mutants have been described previously. 11,12 Rhbdf2 tm1a(KOMP)Wtsi ES cells (MGI:4362881, ...

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“…[12][13] We evaluated the role of these cytokines in the development of experimental HLH. To this end, Unc13d jinx/jinx mutants were bred to Tnf PanR1/PanR1 mice, in which TNF bioactivity is completely abrogated, 8 and to IFN␥ receptor (IFN␥R)-deficient mice. On day 12 after LCMV infection, Unc13d jinx/jinx and Unc13d jinx/jinx ;Tnf PanR1/PanR1 mice had enlarged spleens (supplemental Figure 2A), with elevated proportions of CD8 ϩ T cells and macrophages (supplemental Figure 2B-C).…”

Section: The Development Of Hlh-like Syndrome Is Tnf-independent But mentioning

confidence: 99%

Disruption of MyD88 signaling suppresses hemophagocytic lymphohistiocytosis in mice

Krebs

Crozat

Popkin

et al. 2011

Blood

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IntroductionHemophagocytic lymphohistiocytosis (HLH) is a rare disorder of the immune system. The familial form (FHL) arises in children and is caused by mutations that impair the cytotoxic activity of NK cells and CD8 ϩ T cells. The second form, sporadic HLH, may arise in individuals with pathogen infections or with autoimmune diseases or malignancies. 1 Both HLH variants are believed to be initiated by viral infections. 2 These pathogenic triggers have remained elusive, although Epstein-Barr virus has been proposed as one cause. [3][4] After symptomatic onset of HLH, survival declines rapidly despite chemotherapy with cytotoxic and immunosuppressive drugs. 5 To date, hematopoietic stem cell transplantation is the best long-term therapy for familial HLH.We previously described an N-ethyl-N-nitrosourea (ENU)-germ line mutant called jinx in which a mutation in Unc13d prevents the release of cytolytic granules by NK cells and CD8 ϩ T cells. 6 We demonstrated that clinical features of the HLH-like syndrome observed in humans are recapitulated in Unc13d jinx/jinx mice infected with lymphochoriomeningitis virus (LCMV). Unc13d jinx/jinx remains the only animal model of human type 3 FHL, which is caused by mutations in MUNC13-4, the human ortholog of Unc13d.On infection of Unc13d jinx/jinx mutants, a positive feedback loop is initiated between CD8 ϩ T cells and antigen-presenting cells (APCs) such as macrophages, leading to their overactivation and HLH-like symptoms. 6 We hypothesized that interrupting this positive feedback loop could ameliorate the onset and/or extent of HLH-like disease and potentially reveal novel therapeutic targets for human HLH. We therefore examined the impact of disrupting cell adhesion molecules, effector cytokines, and innate immune sensors on the progression of HLH-like disease in Unc13d jinx/jinx mutants, and identified myeloid differentiation primary response gene 88 (MyD88) as a key protein required for the development of the syndrome. Methods MiceAll mouse studies were performed in accordance with institutional regulations governing animal care and use. C57BL/6J mice were bred locally at The Scripps Research Institute. The following mutants have been previously reported and are described at http://mutagenetix.scripps.edu: For personal use only. on May 10, 2018. by guest www.bloodjournal.org From Complete blood counts and serum cytokine detectionBlood samples were taken from the retro-orbital plexus of mice and analyzed using a Hemavet 950 veterinary hematology system (Fisher Scientific). Alternatively, IFN␥ or TNF were assayed in the serum by ELISA (eBioscience). Viruses, focus-forming unit assayThe Armstrong strain of LCMV was injected intravenously at a dose of 2 ϫ 10 5 plaque-forming units per mouse. Viral titers were determined after organ homogenization by standard plaque assays on VERO cells. Antibodies and intracellular cytokine stainingThe following antibodies were used for flow cytometry, to stain splenocytes: CD11b (M1/70), CD3⑀ (145-2C11), CD8␣ (53-6.7), CD80 (B7-1), CD86 (GL...

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PanR1, a Dominant Negative Missense Allele of the Gene Encoding TNF-α (Tnf), Does Not Impair Lymphoid Development

Cited by 17 publications

References 56 publications

Inflammation and autoimmunity caused by a SHP1 mutation depend on IL-1, MyD88, and a microbial trigger

Inflammation and autoimmunity caused by a SHP1 mutation depend on IL-1, MyD88, and a microbial trigger

iRhom2 is required for the secretion of mouse TNFα

Disruption of MyD88 signaling suppresses hemophagocytic lymphohistiocytosis in mice

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