We investigate danger sensing and innate immune signalling in macrophages, exploring their intricate connections with metabolism, cell death, and cellular structures. Macrophages exhibit fascinating cross-talk related to cell death, as they respond to danger signals released during cellular demise and can themselves engage various genetically defined cell death pathways, each with varying inflammatory potential, some of which are even triggered as a consequence of innate immune signalling. We are especially interested in the sensing mechanism of sterile endogenous or environmental danger signals, and in indirect danger sensing such as involving the effects of pathogens on host cell signalling and function. Metabolism and organelles emerge as information-bearing signalling entities in this context. Our primary focus lies on two families of pattern recognition receptors: inflammasomes and ITAM-coupled receptors that both not only respond to pathogens, but also recognize sterile danger signals. Inflammasomes, nucleated by cytoplasmic receptors, control the unconventional release of interleukin-1 family cytokines and trigger a lytic form of cell death called pyroptosis via activity of their constituent protease caspase-1. ITAM-coupled receptors on the cell surface engage NF-κB transcription factors, leading to macrophage activation and the expression of proinflammatory cytokines, as well as providing an essential inflammasome priming signal. Our investigations of the functional consequences of these mechanisms in the context of host defence, homeostasis, immune pathology, development, and cancer extend to various tissues, including the brain, heart, lung, and bone marrow. Ultimately, our research aims to contribute fundamental insights into the molecular mechanisms of innate immunity and inflammation. By identifying rational targets, we hope to steer immunity and develop control-of-function tools, particularly for cancer-related applications.

10 selected publications

• Tyrosine kinase inhibitors trigger lysosomal damage-associated cell lysis to activate the NLRP3 inflammasome.
  Neuwirt E, Magnani G, Ćiković T, Kostina A, Wöhrle S, Flemming S, Fischer L, Fischenich NJ, Saller BS, Gorka O, Renner S, Agarinis C, Parker C, Boettcher A, Farady CJ, Backofen R, Rodriguez-Franco M, Tholen M, Reinheckel T, Ott T, Groß CJ, Jost PJ, Groß O. (2023)
  Science Signaling 16 (768) DOI: 10.1126/scisignal.abh1083
• Human TH17 cells engage gasdermin E pores to release IL-1α on NLRP3 inflammasome activation.
  Chao YY, Puhach A, Frieser D, Arunkumar M, Lehner L, Seeholzer T, Garcia-Lopez A, van der Wal M, Fibi-Smetana S, Dietschmann A, Sommermann T, Ćiković T, Taher L, Gresnigt MS, Vastert SJ, van Wijk F, Panagiotou G, Krappmann D, Groß O, Zielinski CE. (2023)
  Nat Immunol. 24(2):295-308. doi: 10.1038/s41590-022-01386-w.
• Metabolic reprogramming of donor T cells enhances graft-versus-leukemia effects in mice and humans.
  Uhl FM, Chen S, O'Sullivan D, Edwards-Hicks J, Richter G, Haring E, Andrieux G, Halbach S, Apostolova P, Büscher J, Duquesne S, Melchinger W, Sauer B, Shoumariyeh K, Schmitt-Graeff A, Kreutz M, Lübbert M, Duyster J, Brummer T, Boerries M, Madl T, Blazar BR, Groß O, Pearce EL, and Zeiser R. (2020)
  Sci Transl Med. 12(567):eabb8969.
• The inflammasome drives GSDMD-independent secondary pyroptosis and IL-1 release in the absence of caspase-1 protease activity.
  Schneider KS, Groß CJ, Dreier RF, Saller BS, Mishra R, Gorka O, Heilig R, Meunier E, Dick MS, Cikovic T, Sodenkamp J, Médard G, Naumann R, Ruland J, Kuster B, Broz P, Groß O. (2017).
  Cell Reports 21, 3846-3859.
• K+ efflux-independent NLRP3 inflammasome activation by small molecules targeting mitochondria.
  Groß CJ, Mishra R, Schneider KS, Médard G, Wettmarshausen J, Dittlein DC, Shi H, Gorka O, Koenig PA, Fromm S, Magnani G, Cikovic T, Hartjes L, Smollich J, Robertson AAB, Cooper MA, Schmidt-Supprian M, Schuster M, Schroder K, Broz P, Traidl-Hoffmann C, Beutler B,10 Kuster B, Ruland J, Schneider S, Perocchi F, Groß O (2016).
  Immunity 45, 761-773.
• Inflammasome activators induce interleukin-1α secretion via distinct pathways with differential requirement for the protease function of caspase-1.
  Groß O*, Yazdi AS*, Thomas CJ, Masin M, Heinz LX, Guarda G, Quadroni M, Drexler SK, and Tschopp J (2012).
  Immunity 36, 388-400.
• Recognition of RNA virus by RIG-I results in activation of CARD9 and inflammasome signaling for interleukin 1 beta production.
  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, Ruland J (2010).
  Nat Immunol. 11, 63-69.
• Syk kinase signalling couples to the Nlrp3 inflammasome for anti-fungal host defence.
  Groß O*, Poeck H*, Bscheider M, Dostert C, Hannesschlager N, Endres S, Hartmann G, Tardivel A, Schweighoffer E, Tybulewicz V, Mocsai A, Tschopp J, Ruland J (2009).
  Nature 459, 433-436.
• Card9 controls a non-TLR signalling pathway for innate anti-fungal immunity.
  Groß O, Gewies A, Finger K, Schafer M, Sparwasser T, Peschel C, Forster I, Ruland J (2006).
  Nature 442, 651-656.