Intergrative tissue biology

Head: Prof. Dr. med. Stefan Uderhardt

Our research group is interested in how inflammatory processes arise in tissues and organs and which mechanisms enable them to defend themselves against unwanted, pathological inflammation. To this end, we study the complex cellular and molecular interactions in various inflammatory activated tissues before disease becomes clinically apparent.
In order to better understand the pathomechanisms of chronic inflammation in autoimmune and autoinflammatory diseases such as rheumatoid arthritis, psoriasis or inflammatory bowel diseases such as ulcerative colitis, we investigate to what extent and whether tissues can regenerate completely after an inflammatory flare-up or a successful therapy.

To do this, we use state-of-the-art microscopy techniques that allow us to penetrate deep into interstitial tissue and study immune cells in their natural environment, taking into account the anatomical microenviron-ment. This includes dynamic imaging using 2-photon microscopy, which allows us to observe living immune cells at work and draw functional conclusions directly.

The goal of our research here is to identify novel tissue determinants that define tissues and organs of patients as being at risk for pathological inflammation or recurrence of disease - in order to be able to specifically prevent inflammation.

 

  • The role of tissue-level determinants of inflammation onset, resolution and wound healing.

We hypothesize that a tissue’s particular microenvironment plays a critical role in preventing pathological inflammation as well as in restoring the homeostatic state after resolution.
Using state-of-the-art volumetric imaging techniques in combination with quantitative 3D histocytometric analysis and spatial phenotyping, we seek to determine the molecular and stromal determinants that define the onset of inflammation in peripheral tissues as well as active resolution and subsequent wound healing. Our data will help to better understand the pathomechanisms of chronic diseases and formulate new strategies to address disease at the level of tissue homeostasis.

  • Network synergies in tissue homeostasis and stromal prevention of inflammatory disease.

We hypothesize that prevention of inflammation can be accomplished at the level of tissue homeostasis and cooperative stromal biology. The stroma that underlies any given tissue is not a passive scaffold. Instead it comprises a functional network that regulates key aspects of tissue physiology as an adaptive and self- organising system (homeostat). Resident tissue macrophages (RTM) - the tissue’s very own regulators of inflammation - are physically connected to this homeostat and thereby directly integrated into its cooperative signalling grid. Hard-wired communication mechanisms and synergies allow RTM-stroma networks to operate as a functional syncytium, a hitherto unknown operating system that coordinates stress responses and actively prevents the onset of inflammation. In this ERC-funded project, we employ a pioneering tissue biology approach to decipher the stromal homeostat. By combining unique bioimaging with computational 3D reconstruction and multidimensional profiling, we quantitatively unravel complex cell interactions to explain the mechanisms and implications of stromal network communication in a living tissue. Thereby, we aim to elucidate homeostat-operating principles and establish top-down control of inflammatory tissue checkpoints in order to apply them to clinically relevant inflammatory diseases.

  • Functional adaptations in situ to microenvironmental challenges facilitate neutrophil effector functions in vivo.

Neutrophils are at the forefront of defense and have a highly potent antimicrobial arsenal. They often face extreme conditions and must function in harsh environments such as abscesses. How cells acutely integrate signals to appropriately adapt their effector functions has not been explored, but has far-reaching implications for chronic infectious or sterile inflammatory diseases. In this project, we aim to fill this knowledge gap by using a novel imaging platform that allows visualization of cell dynamics and signaling in neutrophils with high resolution - but in the context of the intact tissue. This experimental setup enables quantitative analysis of neutrophil biology under a variety of controlled microenvironmental perturbations. Together with metabolic and transcriptional profiling, and in situ pathway analysis, we will determine the capacity, but also the limits, of cellular adaptation and investigate molecular drivers previously implicated in the global regulation of neutrophil activation, including HIFs, Src kinases, or GPCR kinases.

 

Stefan UderhardtResearch group leader
Anja WegnerPostdoctoral researcher
Lijian LiScientific doctoral student
Oliver AustScientific doctoral student
Oumaima Ben BrahimScientific doctoral student
Vasco FontesScientific doctoral student
Daniela WeidnerMedical technical assistant
Eric GretoMaster student

Deutsche Forschungsgemeinschaft (DFG)
FOR 2886 - PANDORA “Machine learning-based in vivo assessment of the role of the synovial microenvironment in the pathogenesis of inflammatory arthritis." (2022-2025)

GRK 2740 “Influence of microenvironmental factors on neutrophil effector functions directed against Salmonella enterica serovar Typhimurium.” (2022-2026)

Heisenberg Grant “Assessing tissue-protective functions of macrophages through integrative and functional tissue-level biology.” (2022-2027)

Individual application “Molecular Assessment of the Acute Damage-Response in Stromal Resident Tissue Macrophages.” (2021-2024)

Research Fellowship “Investigations on antigen-dependent and -independent functions of distinct myeloid subsets of phagocytes in host defence and maintenance of self-tolerance during infection and inflammation.” (2014-2016)

European Commission
ERC-Starting Grant „NEXUS - Network Synergies in Tissue Homeostasis and Stromal Prevention of Inflammatory Disease.” (2022-2028)

IZKF, Universitätsklinikum Erlangen
J87 - “Stromal network communication as an immune homeostatic regulatory mechanism." (2021-2023)

Novartis Foundation for Therapeutic Research
„Integrative precision diagnostics in rheumatology: correlation of multimodal joint imaging with quantitative 3D histocytometry of synovial tissues.“ (2021-2024)

 

  1. Uderhardt S, Knopf J, Herrmann M. (2021) Neutrophil swarm control: what goes up must come down. Signal Transduct Target Ther. 6(1):416.
  2. Leppkes M, Lindemann A, Gößwein S, Paulus S, Roth D, Hartung A, Liebing E, Zundler S, Gonzalez-Acera M, Patankar JV, Mascia F, Scheibe K, Hoffmann M, Uderhardt S, Schauer C, Foersch S, Neufert C, Vieth M, Schett G, Atreya R, Kühl AA, Bleich A, Becker C, Herrmann M, Neurath MF. (2021) Neutrophils prevent rectal bleeding in ulcerative colitis by peptidyl-arginine deiminase-4-dependent immunothrombosis. Gut. gutjnl-2021-324725. doi: 10.1136/gutjnl-2021-324725. Online ahead of print.
  3. Faas M, Ipseiz N, Ackermann J, Culemann S, Grüneboom A, Schröder F, Rothe T, Scholtysek C, Eberhardt M, Böttcher M, Kirchner P, Stoll C, Ekici A, Fuchs M, Kunz M, Weigmann B, Wirtz S, Lang R, Hofmann J, Vera J, Voehringer D, Michelucci A, Mougiakakos D, Uderhardt S, Schett G, Krönke G. (2021) IL-33-induced metabolic reprogramming controls the differentiation of alternatively activated macrophages and the resolution of inflammation. Immunity. 54(11):2531-2546.e5. Epub 2021 Oct 12.
  4. Bittel M, Reichert P, Sarfati I, Dressel A, Leikam S, Uderhardt S, Stolzer I, Phu TA, Ng M, Vu NK, Tenzer S, Distler U, Wirtz S, Rothhammer V, Neurath MF, Raffai RL, Günther C, Momma S. (2021) Visualizing transfer of microbial biomolecules by outer membrane vesicles in microbe-host-communication in vivo. J Extracell Vesicles. 10(12):e12159. 
  5. Freeman SA, Uderhardt S, Saric A, Collins RF, Buckley CM, Mylvaganam S, Boroumand P, Plumb J, Germain RN, Ren D, Grinstein S. (2020) Lipid-gated monovalent ion fluxes regulate endocytic traffic and support immune surveillance. Science. 367(6475):301-305. Epub 2019 Dec 5.
  6. Gottschalk RA, Dorrington MG, Dutta B, Krauss KS, Martins AJ, Uderhardt S, Chan W, Tsang JS, Torabi-Parizi P, Fraser ID, Germain RN. (2019) IFN-mediated negative feedback supports bacteria class-specific macrophage inflammatory responses. Elife. 8:e46836.
  7. Uderhardt S, Martins AJ, Tsang JS, Lämmermann T, Germain RN. (2019) Resident Macrophages Cloak Tissue Microlesions to Prevent Neutrophil-Driven Inflammatory Damage. Cell. 177(3):541-555.e17. Epub 2019 Apr 4.
  8. Uderhardt S, Ackermann JA, Fillep T, Hammond VJ, Willeit J, Santer P, Mayr M, Biburger M, Miller M, Zellner KR, Stark K, Zarbock A, Rossaint J, Schubert I, Mielenz D, Dietel B, Raaz-Schrauder D, Ay C, Gremmel T, Thaler J, Heim C, Herrmann M, Collins PW, Schabbauer G, Mackman N, Voehringer D, Nadler JL, Lee JJ, Massberg S, Rauh M, Kiechl S, Schett G, O'Donnell VB, Krönke G. (2017) Enzymatic lipid oxidation by eosinophils propagates coagulation, hemostasis, and thrombotic disease. J Exp Med. 214(7):2121-2138. Epub 2017 May 31.
  9. Pfeifle R, Rothe T, Ipseiz N, Scherer HU, Culemann S, Harre U, Ackermann JA, Seefried M, Kleyer A, Uderhardt S, Haugg B, Hueber AJ, Daum P, Heidkamp GF, Ge C, Böhm S, Lux A, Schuh W, Magorivska I, Nandakumar KS, Lönnblom E, Becker C, Dudziak D, Wuhrer M, Rombouts Y, Koeleman CA, Toes R, Winkler TH, Holmdahl R, Herrmann M, Blüml S, Nimmerjahn F, Schett G, Krönke G. (2017) Regulation of autoantibody activity by the IL-23-TH17 axis determines the onset of autoimmune disease. Nat Immunol. 18(1):104-113. Epub 2016 Nov 7.
  10. Rothe T, Gruber F, Uderhardt S, Ipseiz N, Rössner S, Oskolkova O, Blüml S, Leitinger N, Bicker W, Bochkov VN, Yamamoto M, Steinkasserer A, Schett G, Zinser E, Krönke G. (2015) 12/15-Lipoxygenase-mediated enzymatic lipid oxidation regulates DC maturation and function. J Clin Invest. 125(5):1944-54. Epub 2015 Apr 6.

 

PubMed publication list of Prof. Dr. Stefan Uderhardt