Subproject 1

Inflammasome-associated defects of cytoplasmatic DAMP recognition - Effects of CASP1 gene mutations on transcription, cytokine release patterns and pyroptosis

Inflammasomes are multi-protein complexes that are necessary for the activation of caspase-1. Danger associated molecular patterns (DAMPs) which are recognized by the innate immune system can trigger inflammasome formation. We identified mutations in the pro-caspase-1 encoding CASP1 gene in patients suffering from recurrent febrile episodes that lead to reduced or abrogated enzymatic activity of pro-caspase-1. These mutations were absent or less frequent in healthy control populations. The mutated pro-caspase-1 variants were shown to induce more NF-κB activity via RIP2 interaction than wild type pro-caspase-1 and could thereby contribute to inflammation. The goal of the research project is to elucidate the molecular mechanisms that contribute to the manifestation of autoinflammatory disease in these patients. In particular, we want to characterize the pathways of RIP2 induced NF-κB activation by the pro-caspase-1 variants, and to examine transcriptional changes, altered cytokine secretion as well as pyroptosis in response to proinflammatory stimuli.

Subproject Manager

Staff

Katrin Höhne, MTA
Tel.: 0351-458 6883,
Email: katrin.hoehne

Dr. rer. medic. Hella Luksch, Postdoc
Tel.: 0351-458 6883
Email: hella luksch

Dipl. Biol. Sören Reinke, PhD student
Tel.: 0351-458 6881
Email: soeren.reinke

Susanne Ruß, MTA
Tel. 0351-458 6883
Email: susanne.russ

Dr. rer. medic. Felix Schulze
Tel.: 0351-458 6881
Email: felix schulze

Selected Publications

Bienias M, König N, Wolf C, Kretschmer S, Rösen-Wolff A, Berner R, Tüngler V, Lee-Kirsch MA. Genetic methods for analysis of autoinflammatory diseases. Z Rheumatol. 2017 Apr 4. doi: 10.1007/s00393-017-0300-x. [Epub ahead of print]

Ombrello MJ, Arthur VL, Remmers EF, Hinks A, Tachmazidou I, Grom AA, Foell D, Martini A, Gattorno M, Özen S, Prahalad S, Zeft AS, Bohnsack JF, Ilowite NT, Mellins ED, Russo R, Len C, Hilario MO, Oliveira S, Yeung RS, Rosenberg AM, Wedderburn LR, Anton J, Haas JP, Rosen-Wolff A, Minden K, Tenbrock K, Demirkaya E, Cobb J, Baskin E, Signa S, Shuldiner E, Duerr RH, Achkar JP, Kamboh MI, Kaufman KM, Kottyan LC, Pinto D, Scherer SW, Alarcón-Riquelme ME, Docampo E, Estivill X, Gül A; British Society of Pediatric and Adolescent Rheumatology (BSPAR) Study Group, Inception Cohort of Newly Diagnosed Patients with Juvenile Idiopathic Arthritis (ICON-JIA) Study Group, Childhood Arthritis Prospective Study (CAPS) Group, Randomized Placebo Phase Study of Rilonacept in sJIA (RAPPORT) Investigators, Sparks-Childhood Arthritis Response to Medication Study (CHARMS) Group, Biologically Based Outcome Predictors in JIA (BBOP) Group., Langefeld CD, Thompson S, Zeggini E, Kastner DL, Woo P, Thomson W.. Genetic architecture distinguishes systemic juvenile idiopathic arthritis from other forms of juvenile idiopathic arthritis: clinical and therapeutic implications. Ann Rheum Dis. 2016 Dec 7. pii: annrheumdis-2016-210324. doi: 10.1136/annrheumdis-2016-210324. [Epub ahead of print]

Kallinich T, Thorwarth A, von Stuckrad SL, Rösen-Wolff A, Luksch H, Hundsdoerfer P, Minden K, Krawitz P. Juvenile arthritis caused by a novel FAMIN (LACC1) mutation in two children with systemic and extended oligoarticular course. Pediatr Rheumatol Online J. 2016 Nov 24;14(1):63.

Hofmann SR, Schnabel A, Rösen-Wolff A, Morbach H, Girschick HJ, Hedrich CM. Chronic Nonbacterial Osteomyelitis: Pathophysiological Concepts and Current Treatment Strategies. J Rheumatol. 2016 Nov;43(11):1956-1964.

Stein R, Kapplusch F, Heymann MC, Russ S, Staroske W, Hedrich CM, Rösen-Wolff A, Hofmann SR. Enzymatically Inactive Procaspase 1 stabilizes the ASC Pyroptosome and Supports Pyroptosome Spreading during Cell Division. J Biol Chem. 2016 Aug 26;291(35):18419-29.

Winkler S, Hedrich CM, Rösen-Wolff A. Caspase-1 regulates autoinflammation in rheumatic diseases. Z Rheumatol. 2016 Apr;75(3):265-75.

Eberhardt CS, Haas JP, Girschick H, Schwarz T, Morbach H, Rösen-Wolff A, Foell D, Dannecker G, Schepp C, Ganser G, Honke N, Eggermann T, Müller-Berghaus J, Wagner N, Ohl K, Tenbrock K. No association of IL-12p40 pro1.1 polymorphism with juvenile idiopathic arthritis. Pediatr Rheumatol Online J. 2015 Dec 15;13:61.

Hofmann SR, Kubasch AS, Ioannidis C, Rösen-Wolff A, Girschick HJ, Morbach H, Hedrich CM. Altered expression of IL-10 family cytokines in monocytes from CRMO patients result in enhanced IL-1β expression and release. Clin Immunol. 2015 Dec;161(2):300-7.

Hauck F, Magerus-Chatinet A, Vicca S, Rensing-Ehl A, Roesen-Wolff A, Roesler J, Rieux-Laucat F. Somatic loss of heterozygosity, but not haploinsufficiency alone, leads to full-blown autoimmune lymphoproliferative syndrome in 1 of 12 family members with FAS start codon mutation. Clin Immunol. 2013 Apr;147(1):61-8.

Winkler S and Rösen-Wolff A. Caspase-1: An integral regulator of innate immunity. Semin Immunopathol. 2015 Jul;37(4):419-27.

Heymann MC, Rabe S, Ruß S, Kapplusch F, Schulze F, Stein R, Winkler S, Hedrich CM, Rösen-Wolff A, Hofmann SR. Fluorescent tags influence the enzymatic activity and subcellular localization of procaspase-1. Clin Immunol. 2015 Oct;160(2):172-9.

Luksch H, Winkler S, Heymann MC, Schulze F, Hofmann SR, Roesler J, Rösen-Wolff A. Current knowledge on procaspase-1 variants with reduced or abrogated enzymatic activity in autoinflammatory disease. Curr Rheumatol Rep. 2015;17(7):520-527.

Knaack S, Lode A, Hoyer B, Rösen-Wolff A, Gabrielyan A, Roeder I, Gelinsky M. Heparin modification of a biomimetic bone matrix for controlled release of VEGF. J Biomed Mater Res A. 2014;102(10):3500-11.

Gabrielyan A, Knaak S, Gelinsky M, Arnhold S, Rösen-Wolff A. Hypoxia-conditioned media allows species-specific attraction of bone marrow stromal cells without requirement for recombinant proteins. BMC Veterinary Research. 2014 Mar 4;10:56.

Heymann MC, Winkler S, Luksch H, Flecks S, Franke M, Ruß S, Özen S, Yilmaz E, Klein C, Kallinich T, Lindemann D, Brenner S, Ganser G, Roesler J, Rösen-Wolff A, Hofmann SR. Human procaspase-1 variants with decreased enzymatic activity are associated with febrile episodes and may contribute to inflammation via RIP2 and NFkB signaling. J Immunol. 2014;192(9):4379-85.

Kretschmer S, Wolf C, König N, Staroske W, Guck J, Häusler M, Luksch H, Nguyen LA, Kim B, Alexopoulou D, Dahl A, Rapp A, Cardoso MC, Shevchenko A, Lee-Kirsch MA. SAMHD1 prevents autoimmunity by maintaining genome stability. Ann Rheum Dis. 2015 Mar;74(3):e17.

Heymann M, Winkler S, Özen S, Yilmaz E, Kallinich T, Rösen-Wolff A, Roesler J, Hofmann S. Procaspase-1 contributes to inflammation via NF-KB. Pediatric Rheumatology 2013:11(Suppl 1):A251.

Lesche M, Dahl A, Kränkel A, Roesler J, Rösen-Wolff A. Low frequency variants of NLRP3 in CAPS patients. Pediatric Rheumatology 2013:11(Suppl 1):A167.

Luksch H, Schlipfenbacher V, Winkler S, Roesler J, Rösen-Wolff A. Caspase-1 variants involved in ER stress. Pediatric Rheumatology 2013:11(Suppl 1):A252.

Hermsdorf A, Pessler F, Luksch H, Winkler S, Naumann R, Roesler J, Roers A, Rösen-Wolff A. A transgenic mouse model for variant procaspase-1. Pediatric Rheumatology 2013:11(Suppl 1):A250.

Rabe S, Heymann MC, Russ S, Winkler S, Roesler J, Rösen-Wolff A, Hofmann SR. CASP1 variants and live cell imaging. Pediatric Rheumatology 2013:11(Suppl 1):A253.

Peschke K, Friebe F, Zimmermann N, Wahlicht T, Schumann T, Achleitner M, Berndt N, Luksch H, Behrendt R, Lee-Kirsch MA, Roers A, Günther C. Deregulated Type I IFN Response in TREX1-Associated Familial Chilblain Lupus. J Invest Dermatol. 2014 May;134(5):1456-9.

Luksch H, Romanowski MJ, Chara O, Tüngler V, Caffarena ER, Heymann MC, Lohse P, Aksentijevich I, Remmers EF, Flecks S, Quoos N, Gramatté J, Petzold C, Hofmann SR, Winkler S, Pessler F, Kallinich T, Ganser G, Nimtz-Talaska A, Baumann U, Runde V, Grimbacher B, Birmelin J, Gahr M, Roesler J, Rösen-Wolff A. Naturally occurring genetic variants of human caspase-1 differ considerably in structure and the ability to activate interleukin-1β. Hum Mutat 2013; 34(1):122-31.

Heymann MC, Rösen-Wolff A. Contribution of the inflammasomes to autoinflammatory diseases and recent mouse models as research tools. Clin Immunol 2013;147(3):175-84.

Winkler S, van Leeuwen K, Deboer M, Rösen-Wolff A, Roos D, Roesler J. Alu repeat-induced deletions in chronic granulomatous disease: a cause not only for p67-phox, but also for p47-phox deficiency. Ann Hematol 2013;92(7):1003-4.

Winkler S, Heymann MC, Franke M, Martin A, Roesler J, Rösen-Wolff A. A protective role for inflammasome activation following injury. Shock 2012; 37(6):659.

Groessl M, Luksch H, Rösen-Wolff A, Shevchenko A, Gentzel M. Profiling of the human monocytic cell secretome by quantitative label-free mass spectrometry identifies stimulus-specific cytokines and proinflammatory proteins. J Proteomics 2012; 12(18):2833-42.

Hedrich CM, Bruck N, Paul D, Hahn G, Gahr M, Rösen-Wolff A. “Mutation negative" Familial Cold Autoinflammatory Syndrome (FCAS) in an 8-year-old boy - Clinical course and functional studies. Rheumatol Internat (Clinical and Experimental Investigations) 2012; 32(9):2629-36.

Hofmann SR, Morbach H, Schwarz T, Rösen-Wolff A, Girschick HJ, Hedrich CM. Attenuated TLR4/MAPK signaling in monocytes from patients with CRMO results in impaired IL-10 expression. Clin Immunol 2012; 145(1):69-76.

Seckinger A, Meissner T, Moreaux J, Depeweg D, Hillengass J, Hose K, Rème T, Rösen-Wolff A, Jauch A, Schnettler R, Ewerbeck V, Goldschmidt H, Klein B, Hose D. Clinical and prognostic role of annexin A2 in multiple myeloma. Blood 2012; 120(5):1087-94.

Roesler J, Segerer F, Morbach H, Kleinert S, Thieme S, Rösen-Wolff A, Liese JG. P67-phox (NCF2) lacking exons 11 and 12 is functionally active and leads to an extremely late diagnosis of chronic granulomatous disease (CGD). PLoS One 2012; 7(4):e34296.

Hofmann SR, Rösen-Wolff A, Tsokos GC, Hedrich CM. Biological properties and regulation of IL-10 related cytokines and their contribution to autoimmune disease and tissue injury. Clin Immunol 2012; 143(2):116-27.

Hofmann SR, Roesen-Wolff A, Hahn G, Hedrich CM. Update: Cytokine Dysregulation in Chronic Nonbacterial Osteomyelitis (CNO). Int J Rheumatol 2012; 2012:310206.

Hofmann SR, Möller J, Rauen T, Paul D, Gahr M, Rösen-Wolff A, Brenner S, Hedrich CM. Dynamic CpG-DNA methylation of Il10 and Il19 in CD4+ T lymphocytes and macrophages: effects on tissue-specific gene expression. Klin Padiatr 2012; 224(2):53-60.

Roesler J, Rösen-Wolff A. Redundant ability of phagocytes to kill Aspergillus species. J Allergy Clin Immunol 2011; 128(3):686-7; author reply 687-8.

Liu L, Okada S, Kong XF, Kreins AY, Cypowyj S, Abhyankar A, Toubiana J, Itan Y, Audry M, Nitschke P, Masson C, Toth B, Flatot J, Migaud M, Chrabieh M, Kochetkov T, Bolze A, Borghesi A, Toulon A, Hiller J, Eyerich S, Eyerich K, Gulácsy V, Chernyshova L, Chernyshov V, Bondarenko A, Grimaldo RM, Blancas-Galicia L, Beas IM, Roesler J, Magdorf K, Engelhard D, Thumerelle C, Burgel PR, Hoernes M, Drexel B, Seger R, Kusuma T, Jansson AF, Sawalle-Belohradsky J, Belohradsky B, Jouanguy E, Bustamante J, Bué M, Karin N, Wildbaum G, Bodemer C, Lortholary O, Fischer A, Blanche S, Al-Muhsen S, Reichenbach J, Kobayashi M, Rosales FE, Lozano CT, Kilic SS, Oleastro M, Etzioni A, Traidl-Hoffmann C, Renner ED, Abel L, Picard C, Maródi L, Boisson-Dupuis S, Puel A, Casanova JL. Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis. J Exp Med 2011; 208(8):1635-48.

Kuemmerle-Deschner JB, Ramos E, Blank N, Roesler J, Felix SD, Jung T, Stricker K, Chakraborty A, Tannenbaum S, Wright AM, Rordorf C. Canakinumab (ACZ885, a fully human IgG1 anti-IL-1β mAb) induces sustained remission in pediatric patients with cryopyrin-associated periodic syndrome (CAPS). Arthritis Res Ther 2011; 13(1):R34.

Metzler KD, Fuchs TA, Nauseef WM, Reumaux D, Roesler J, Schulze I, Wahn V, Papayannopoulos V, Zychlinsky A. Myeloperoxidase is required for neutrophil extracellular trap formation: implications for innate immunity. Blood 2011; 117(3):953-9.

Hofmann SR, Heymann MC, Hermsdorf A, Rösen-Wolff A. Recent Advances in Autoinflammatory Diseases and Animal Models. J Genet Syndr Gene Ther 2011; S:3. dx.doi.org/10.4172/2157-7412.S3-002.

Hofmann SR, Schwarz T, Möller JC, Morbach H, Schnabel A, Rösen-Wolff A, Girschick HJ, Hedrich CM. Chronic non-bacterial osteomyelitis is associated with impaired Sp1 signaling, reduced IL10 promoter phosphorylation, and reduced myeloid IL-10 expression. Clin Immunol 2011; 141(3):317-27.

Roesler J, Hedrich C, Laass MW, Heyne K, Rösen-Wolff A. Meningoencephalitis caused by varicella zoster virus reactivation in a child with dominant partial interferon-gamma receptor-1 deficiency. Pediatr Infect Dis J 2011; 30(3):265-6.

Möller JC, Paul D, Ganser G, Range U, Gahr M, Kelsch R, Rösen-Wolff A, Hedrich CM. IL10 promoter polymorphisms are associated with systemic onset juvenile idiopathic arthritis (SoJIA). Clin Exp Rheumatol 2010; 8(6):912-8.

Bernhardt A, Thieme S, Domaschke H, Springer A, Rösen-Wolff A, Gelinsky M. Crosstalk of osteoblast and osteoclast precursors on mineralized collagen--towards an in vitro model for bone remodeling. J Biomed Mater Res A 2010; 95(3):848-56.

SchimkeLF, SawalleJ,Roesler J, Wollenberg A, Rack A, Borte M, Rieber N, Cremer R, Maaß E, Dopfer R, Reichenbach J, Wahn V, Hoenig M, Jansson AF, Roesen-WolffA, Schaub B, Seger R, Hill HR, Ochs HD, Torgerson TR, Belohradsky BH, Renner ED. Diagnostic approach to the hyper-IgE syndromes (HIES) Immunological and clinical key findings to differentiate HIES from atopic dermatitis. J Allergy Clin Immunol 2010; 126:611-7.

Freudenberg F, Wintergerst U, Roesen-Wolff A, Albert MH, Prell C, Strahm B, Koletzko S, Ehl S, Roos D, Tommasini A, Ventura A, Belohradsky BH, Seger R, Roesler J, Güngör T. Therapeutic strategy in p47-phox deficient chronic granulomatous disease presenting as inflammatory bowel disease. J Allergy Clin Immunol 2010; 125(4):943-6.

Gentsch M, Kaczmarczyk A, van Leeuwen K, de Boer M, Kaus-Drobek M, Dagher MC, Kaiser P, Arkwright PD, Gahr M, Rösen-Wolff A, Bochtler M, Secord E, Britto-Williams P, Saifi GM, Maddalena A, Dbaibo G, Bustamante J, Casanova JL, Roos D, Roesler J. Alu-repeat-induced deletions within the NCF2 gene causing p67-phox-deficient chronic granulomatous disease (CGD). Hum Mutat 2010; 31(2):151-8.

Subproject 1

Prof. Dr. med. Angela Rösen-Wolff

Dr. med. Stefan Winkler (2. Förderphase)

Priv.-Doz. Dr. med. Joachim Roesler (1. Förderphase)

Staff

Selected Publications

Dr. med. Stefan Winkler
(2. Förderphase)

Priv.-Doz. Dr. med. Joachim Roesler
(1. Förderphase)