Abstract
Blau syndrome (BS) is a rare familial granulomatous disease manifested by uveitis, arthritis and skin rash. BS has recently been found to be associated with a distinctive mutation in NOD2, which encodes an intracellular toll-like receptor. We have compared host cell interaction with bacterial challenge in U937 cells expressing wild type human NOD2 (NOD2wt), mutant NOD2 (NOD2Blau), or a vector control (VC). The cells were incubated with Salmonella typhimurium. Intracellular uptake was assessed by harvesting the cells at different time points following invasion and quantitating the CFU, recovered after gentamicin treatment to kill extracellular organisms. Expression of TNF-α, TLR2 and TLR4 was determined by semi-quantitative RT-PCR under resting conditions and after stimulation by bacteria. Invasion of target cells with S. typhimurium was diminished in the presence of NOD2Blau. Expression of TNF-α mRNA was enhanced following bacterial invasion in all cell lines but NOD2Blau was associated with a more rapid decline in TNF-α expression. Kinetics of intracellular clearance of bacteria indicated a relative defect in NOD2Blau compared to controls. This clearance defect may be related to the lack of sustained TNF-α seen in the early stages. These events were not related to differential TLR2 or TLR4 expression since there were no significant differences seen between the cell lines after bacterial stimulation. Our findings indicate that the NOD2 mutation associated with this syndrome alters host:microbial interaction, and this may have relevance to triggering factors in the ocular and joint inflammation seen in BS.
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References
Inohara N, Nunez G (2003) NODs: intracellular proteins involved in inflammation and apoptosis. Nat Rev Immunol 3:371–382
Inohara N, Nunez G (2001) The NOD: a signaling module that regulates apoptosis and host defense against pathogens. Oncogene 20:6473–6481
Girardin SE, Boneca IG, Viala J et al (2003) Nod2 is a general sensor of peptidoglycan through muramyl dipeptide (MDP) detection. J Biol Chem 11:8869–8872
Inohara N, Ogura Y, Fontalba A et al (2003) Host recognition of bacterial murayl dipeptide medicated through NOD2. J Biol Chem 278:5509–5512
Ogura Y, Inohara N, Benito A, Chen FF, Yamaoka CS, Nunez G (2001) Nod2, a Nod1/Apaf-1 family member that is restricted to monocytes and activates NF-κB. J Biol Chem 276:4812–4818
Hugot JP, Chamallard M, Zouall H et al (2001) Association of Nod2 leucine-rich repeat variants with susceptibility to Crohn’s disease. Nature 411:599–602
Ogura Y, Bonen DK, Inohara N et al (2001) A frameshift mutation in NOD2 associated with susceptibility to Crohn’s disease. Nature 411:603–606
Hisamatsu T, Suzuki M, Reinecker H, Nadeau WJ, Mccormick BA, Podolsky DK (2003) CARD15/NOD2 functions as an antibacterial factor in human intestinal epithelial cells. Gastroenterology 124:993–1000
Miceli-Richard C, Lesage S, Rybojad M et al (2001) CARD 15 mutations in Blau syndrome. Nat Genet 29:19–20
Wang X, Kuivaniemi H, Bonavita G et al (2002) Card15 mutations in familial granulomatosis syndromes. Arthritis Rheum 46:3041–3045
Costa JC, Benson JM, Seroogy CM, Achacoso P, Fathman CG, Nolan GP (2000) Targeting rare populations of murine antigen-specific T lymphocytes by retroviral transduction for potential application in gene therapy for autoimmune disease. J Immunol 164:3581–3590
Ogura Y, Lala S, Xin W et al (2003) Expression of NOD2 in Paneth cells: a possible link to Crohn’s ileitis. Gut 52:1591–1597
Penttinen MA, Holmberg CI, Sistonen L, Granfors K (2002) HLA-B27 modulates nuclear factor κB activation in human monocytic cells exposed to lipopolysaccharide. Arthritis Rheum 46:2172–2180
Inman RD, Payne U (2003) Determinants of synoviocyte clearance of arthritogenic bacteria. J Rheumatol 30:1291–1297
Inohara N, Ogura Y, Nunez G (2002) Nods: a family of cytosolic proteins that regulate the host response to pathogens. Curr Opin Microbial 5:76–80
Hampe J, Cuthbert A, Croucher PJ et al (2001) Association between insertion mutation in NOD2 gene and Corhn’s disease in German and British populations. Lancet 357:1925–1928
Zhao YX, Zhang H, Chiu B, Payne U, Inman RD (1999) Tumor necrosis factor receptor p55 controls the severity of arthritis in experimental Yersinia enterocolitica infection. Arthritis Rheum 42:1662–1672
Inman RD, Whittum-Hudson JA, Schumacher HR, Hudson AP (2000) Chlamydia and associated with arthritis. Curr Opin Rheumatol 12:254–262
Girardin SE, Boneca IG, Carneiro LA et al (2003) Nod1 detects a unique muropeptide from gram negative bacterial peptidoglycan. Science 300:1584–1587
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Kim, TH., Payne, U., Zhang, X. et al. Altered host:pathogen interactions conferred by the Blau syndrome mutation of NOD2 . Rheumatol Int 27, 257–262 (2007). https://doi.org/10.1007/s00296-006-0250-0
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DOI: https://doi.org/10.1007/s00296-006-0250-0