Regulated inflammatory responses facilitate host defense and efficient wound healing. However, chronic or excessive inflammation can be pathogenic, as seen in gout, inflammatory bowel disease, neurodegenerative diseases like multiple sclerosis or Alzheimer’s, and metabolic diseases such as atherosclerosis and certain forms of diabetes. In addition, inflammation can drive the progression of certain types of cancer. Inflammation is initiated and orchestrated by secreted factors, including the interleukin-1 (IL-1) protein family members IL-1α and IL-1β. In contrast to most other cytokines, they lack signal peptides and are therefore synthesized in the cytoplasm and secreted by an unconventional, endoplasmic reticulum-Golgi-independent mechanism. Caspase-1-mediated cleavage of IL-1β is required for its binding to IL-1 receptor 1, and thus for it’s bioactivity. Caspase-1 itself is activated through cytoplasmic protein complexes called inflammasomes that respond to numerous signals of cellular stress and infection. Since IL-1β is found extracellularly primarily in its cleaved form and since inflammasome-deficient cells fail to secrete IL-1β, it was assumed that IL-1β cleavage is a prerequisite for its secretion. In contrast, IL-1α is active in its unprocessed form but like IL-1β still requires secretion from its source cell in order to reach its receptor. Recently, we and others showed that even though IL-1α is not a substrate of caspase-1, caspase-1 can control its secretion, opening the possibility that caspase-1 might control the secretion of other non-substrate proteins. Using the tools of systems biology, we study the molecular mechanisms of inflammasome activation and inflammasome-induced protein secretion, as well as the proteins subject to this secretion pathway. A better understanding of these events could lead to the development of new therapeutic strategies for the treatment of chronic inflammatory deceases.

Katharina Schneider, Dipl.Mol.Med.
Christina Thomas, M.Sc.
Susanne Weiß, T.A.

Neumann K,  Castiñeiras-Vilariño M, Höckendorf U, Hannesschläger N, Lemeer S, Kupka D, Meyermann S, Lech M, Anders HJ, Kuster B, Busch DH, Gewies A, Naumann R, Groß O, Ruland J (2014). Clec12a is an inhibitory receptor for uric acid crystals that regulates inflammation in response to cell death. Immunology 40(3):389-399.

Yabal M, Müller N, Adler H, Knies N, Groß CJ, Damgaard RB, Kanegane H, Ringelhan M, Kaufmann T, Heikenwälder M, Strasser A, Groß O, Ruland J, Peschel C, Gyrd-Hansen M, Jost PJ (2014). XIAP restricts TNF- and RIP3-dependent cell death and inflammasome activation. Cell Reports 7(6):1796-1808.  

Shahzad K, Bock F, Dong W, Wang H, Kopf S, Kohli S, Al-Dabet MM, Ranjan S, Wolter J, Wacker C, Biemann R, Stoyanov S, Reymann K, Söderkvist P, Groß O, Schwenger V, Pahernik S, Nawroth PP, Gröne HJ, Madhusudhan T, Isermann B (2014). Nlrp3-inflammasome activation in non-myeloid-derived cells aggravates diabetic nephropathy. Kidney Int. [Epub ahead of print]

Schweneker K, Gorka O, Schweneker M, Poeck H, Tschopp J, Peschel C, Ruland J, Gross O (2013). The mycobacterial cord factor adjuvant analogue trehalose-6,6'-dibehenate (TDB) activates the Nlrp3 inflammasome. Immunobiology 218(4):664-673.

Gewies A, Castineiras-Vilarino M, Ferch U, Jährling N, Heinrich K, Hoeckendorf U, Przemeck GK, Munding M, Groß O, Schroeder T, Horsch M, Karran EL, Majid A, Antonowicz S, Beckers J, Hrabé de Angelis M, Dodt HU, Peschel C, Förster I, Dyer MJ, Ruland J (2013). Prdm6 is essential for cardiovascular development in vivo. PLoS One 8(11):e81833. 

Gross, O., Yazdi, A.S., Thomas, C.J., Masin, M., Heinz, L.X., Guarda, G., Quadroni, M., Drexler, S.K., and Tschopp, J. (2012). Inflammasome Activators Induce Interleukin-1a Secretion via Distinct Pathways with Differential Requirement for the Protease Function of Caspase-1. Immunity 36, 388–400.

Vince, J.E., Wong, W.W., Gentle, I., Lawlor, K.E., Allam, R., O'Reilly, L., Mason, K., Gross, O., Ma, S., Guarda, G., Anderton, H., Castillo, R., Hacker, G., Silke, J., and Tschopp, J. (2012). Inhibitor of Apoptosis Proteins Limit RIP3 Kinase-Dependent Interleukin-1 Activation. Immunity 36, 215-227.

Heinz, L.X., Rebsamen, M., Rossi, D.C., Staehli, F., Schroder, K., Quadroni, M., Gross, O., Schneider, P., and Tschopp, J. (2012). The death domain-containing protein Unc5CL is a novel MyD88-independent activator of the pro-inflammatory IRAK signaling cascade. Cell Death Differ 19, 722-731.

Hafalla, J.C., Burgold, J., Dorhoi, A., Gross, O., Ruland, J., Kaufmann, S.H., and Matuschewski, K. (2012). Experimental cerebral malaria develops independently of caspase recruitment domain-containing protein 9 signaling. Infect Immun 80, 1274-1279.

Gross, O. (2012). Measuring the inflammasome. Methods Mol Biol 844, 199-222.

Dorhoi, A., Nouailles, G., Jorg, S., Hagens, K., Heinemann, E., Pradl, L., Oberbeck-Muller, D., Duque-Correa, M.A., Reece, S.T., Ruland, J., Brosch, R., Tschopp, J., Gross, O., and Kaufmann, S. H. (2012). Activation of the NLRP3 inflammasome by Mycobacterium tuberculosis is uncoupled from susceptibility to active tuberculosis. European Journal of Immunology 42, 374-384.

Gross, O., Thomas, C.J., Guarda, G., and Tschopp, J. (2011). The inflammasome: an integrated view. Immunol Rev 243, 136-151.

Ritter, M., Gross, O., Kays, S., Ruland, J., Nimmerjahn, F., Saijo, S., Tschopp, J., Layland, L.E., and Prazeres da Costa, C. (2010). Schistosoma mansoni triggers Dectin-2, which activates the Nlrp3 inflammasome and alters adaptive immune responses. Proc Natl Acad Sci U S A 107, 20459-20464.

Poeck, H., Bscheider, M., Gross, O., Finger, K., Roth, S., Rebsamen, M., Hannesschlager, N., Schlee, M., Rothenfusser, S., Barchet, W., Kato, H., Akira, S., Inoue, S., Endres, S., Peschel, C., Hartmann, G., Hornung, V., and Ruland, J. (2010). Recognition of RNA virus by RIG-I results in activation of CARD9 and inflammasome signaling for interleukin 1 beta production. Nature Immunology 11, 63-69.

Ng, J., Hirota, S.A., Gross, O., Li, Y., Ulke-Lemee, A., Potentier, M.S., Schenck, L.P., Vilaysane, A., Seamone, M.E., Feng, H., Armstrong, G. D., Tschopp, J., Macdonald, J. A., Muruve, D. A., and Beck, P. L. (2010). Clostridium difficile toxin-induced inflammation and intestinal injury are mediated by the inflammasome. Gastroenterology 139, 542-552, 552 e541-543.

Dorhoi, A., Desel, C., Yeremeev, V., Pradl, L., Brinkmann, V., Mollenkopf, H.J., Hanke, K., Gross, O., Ruland, J., and Kaufmann, S.H. (2010). The adaptor molecule CARD9 is essential for tuberculosis control. The Journal of Experimental Medicine 207, 777-792.

Arlehamn, C.S., Petrilli, V., Gross, O., Tschopp, J., and Evans, T.J. (2010). The role of potassium in inflammasome activation by bacteria. The Journal of Biological Chemistry 285, 10508-10518.

Werninghaus, K., Babiak, A., Gross, O., Holscher, C., Dietrich, H., Agger, E.M., Mages, J., Mocsai, A., Schoenen, H., Finger, K., Nimmerjahn, F., Brown, G. D., Kirschning, C., Heit, A., Andersen, P., Wagner, H., Ruland, J., and Lang, R. (2009). Adjuvanticity of a synthetic cord factor analogue for subunit Mycobacterium tuberculosis vaccination requires FcRgamma-Syk-Card9-dependent innate immune activation. J Exp Med 206, 89-97.

Steinberg, C., Eisenacher, K., Gross, O., Reindl, W., Schmitz, F., Ruland, J., and Krug, A. (2009). The IFN regulatory factor 7-dependent type I IFN response is not essential for early resistance against murine cytomegalovirus infection. Eur J Immunol 39, 1007-1018.

Robinson, M.J., Osorio, F., Rosas, M., Freitas, R.P., Schweighoffer, E., Gross, O., Verbeek, J.S., Ruland, J., Tybulewicz, V., Brown, G.D., Moita, L. F., Taylor, P. R., and Reis e Sousa, C. (2009). Dectin-2 is a Syk-coupled pattern recognition receptor crucial for Th17 responses to fungal infection. The Journal of Experimental Medicine 206, 2037-2051.

Gross, O., Poeck, H., Bscheider, M., Dostert, C., Hannesschlager, N., Endres, S., Hartmann, G., Tardivel, A., Schweighoffer, E., Tybulewicz, V., Mocsai, A., Tschopp, J., and Ruland, J. (2009). Syk kinase signalling couples to the Nlrp3 inflammasome for anti-fungal host defence. Nature 459, 433-436.

Glocker, E.O., Hennigs, A., Nabavi, M., Schaffer, A.A., Woellner, C., Salzer, U., Pfeifer, D., Veelken, H., Warnatz, K., Tahami, F., Jamal, S., Manguiat, A., Rezaei, N., Amirzargar, A. A., Plebani, A., Hannesschlager, N., Gross, O., Ruland, J., and Grimbacher, B. (2009). A homozygous CARD9 mutation in a family with susceptibility to fungal infections. The New England Journal of Medicine 361, 1727-1735.

Dostert, C., Guarda, G., Romero, J.F., Menu, P., Gross, O., Tardivel, A., Suva, M.L., Stehle, J.C., Kopf, M., Stamenkovic, I., Corradin, G., and Tschopp, J. (2009). Malarial hemozoin is a Nalp3 inflammasome activating danger signal. PLoS One 4, e6510.

Gross, O., Grupp, C., Steinberg, C., Zimmermann, S., Strasser, D., Hannesschlager, N., Reindl, W., Jonsson, H., Huo, H., Littman, D.R., Peschel, C., Yokoyama, W. M., Krug, A., and Ruland, J. (2008). Multiple ITAM-coupled NK-cell receptors engage the Bcl10/Malt1 complex via Carma1 for NF-kappaB and MAPK activation to selectively control cytokine production. Blood 112, 2421-2428.

LeibundGut-Landmann, S., Gross, O., Robinson, M.J., Osorio, F., Slack, E.C., Tsoni, S.V., Schweighoffer, E., Tybulewicz, V., Brown, G.D., Ruland, J., and Reis e Sousa, C. (2007). Syk- and CARD9-dependent coupling of innate immunity to the induction of T helper cells that produce interleukin 17. Nature Immunology 8, 630-638.

Jost, P.J., Weiss, S., Ferch, U., Gross, O., Mak, T.W., Peschel, C., and Ruland, J. (2007). Bcl10/Malt1 signaling is essential for TCR-induced NF-kappaB activation in thymocytes but dispensable for positive or negative selection. Journal of Immunology 178, 953-960.

Gross, O., Gewies, A., Finger, K., Schafer, M., Sparwasser, T., Peschel, C., Forster, I., and Ruland, J. (2006). Card9 controls a non-TLR signalling pathway for innate anti-fungal immunity. Nature 442, 651-656.