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DFG Collaborative Research Centre 1444

This Collaborative Research Centre aims to unravel the basic mechanisms that differentiate between success and failure in regeneration of musculoskeletal tissue using bone healing as a role model.

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Subproject 11 - Principal Investgators

Innate immune circuits for bone maintenance and regeneration

Bones are an integral part of our skeleton and provide a frame, protection and stability for our organism. Bones are dynamic tissues and turnover occurs constantly at homeostasis and is impaired in various conditions including aging, pregnancy and metabolic disease, leading to a high risk for fracture and impaired bone healing. We have shown (Schaupp, Cell 2020) that innate cell-derived cytokines such as type I interferons are regulated by the microbiota and control the metabolism and function of a wide range of mononuclear phagocytes (e.g., dendritic cells, microglia, macrophages). Osteoclasts are bone-resorbing macrophages, but the contribution of such pathways to bone regeneration remains unknown. In addition, we have investigated mechanisms by which TNF regulates osteoclast formation by controlling the pre-osteoclast pool. How innate cell-derived cytokines control the ability of osteoclast precursors to form osteoclasts remains largely unknown. To address this, we systematically investigate the role of innate cytokines and the microbiota as regulators of osteoclastogenesis. A second line of research interrogates how mononuclear phagocyte subsets and tissue-resident innate lymphoid cells (ILCs) regulate the pre-osteoclast pool, thus modulating bone homeostasis or bone repair. Finally, we are investigating the role of ILC in the small intestine for the uptake of nutrients and salts that are needed for bone homeostasis at steady-state but also during pregnancy, a state of hightened bone metabolism. Our goal is to unravel how innate and microbiota-dependent pathways control bone regeneration at homeostasis, in pregnancy and in the context of compromised healing.

Most important results

Tissue circuits controlling macrophage activation

Inflammatory Response | Energy Supply & Consumption

Elevated type I interferons regulate tissue macrophages by activating a population of NKp46+ ILCs.

In collaboration with subproject P14

TGF-β regulates the function of ILC

Inflammatory Response | Energy Supply & Consumption

TGF-β a cytokine that plays important roles for bone homeostasis dysregulates innate immune responses to viral infections.

Witkowski et al., Nature 2021 | Incollaboration with subproject P13

Role of ILC in regulating bone homeostasis

Inflammatory Response | Energy Supply & Consumption

ILCs regulate uptake of nutrients required for bone homeostasis during pregnancy.


Stylianos Gnafakis (Doctoral Researcher)

ILC and bone metabolism during pregnancy

Dr. Atsuyo Ikeda (Clinician Scientist)

ILC and bone metabolism

Ana Kasapi (Doctoral Researcher)

Regulation of Osteoclastogenesis by the DNA Damage Response

Anita Kowalcyzk (Doctoral Researcher)

The role of ILC in vascular function and angiogenesis


  • Mattiola, I.; Diefenbach, A.

    Regulation of innate immune system function by the microbiome: Consequences for tumor immunity and cancer immunotherapy

    Semin Immunol 2023; 66:101724.
  • Jarick, K. J.; Topczewska, P. M.; Jakob, M. O.; Yano, H.; Arifuzzaman, M.; Gao, X.; Boulekou, S.; Stokic-Trtica, V.; Leclere, P. S.; Preusser, A.; Rompe, Z. A.; Stamm, A.; Tsou, A. M.; Chu, C.; Heinrich, F. R.; Guerra, G. M.; Durek, P.; Ivanov, A.; Beule, D.; Helfrich, S.; Duerr, C. U.; Kuhl, A. A.; Stehle, C.; Romagnani, C.; Mashreghi, M. F.; Diefenbach, A.; Artis, D.; Klose, C. S. N.

    Non-redundant functions of group 2 innate lymphoid cells

    Nature 2022; 611(7937):794-800.
  • Witkowski, M.; Tizian, C.; Ferreira-Gomes, M.; Niemeyer, D.; Jones, T. C.; Heinrich, F.; Frischbutter, S.; Angermair, S.; Hohnstein, T.; Mattiola, I.; Nawrath, P.; McEwen, S.; Zocche, S.; Viviano, E.; Heinz, G. A.; Maurer, M.; Kolsch, U.; Chua, R. L.; Aschman, T.; Meisel, C.; Radke, J.; Sawitzki, B.; Roehmel, J.; Allers, K.; Moos, V.; Schneider, T.; Hanitsch, L.; Mall, M. A.; Conrad, C.; Radbruch, H.; Duerr, C. U.; Trapani, J. A.; Marcenaro, E.; Kallinich, T.; Corman, V. M.; Kurth, F.; Sander, L. E.; Drosten, C.; Treskatsch, S.; Durek, P.; Kruglov, A.; Radbruch, A.; Mashreghi, M. F.; Diefenbach, A.

    Untimely TGFbeta responses in COVID-19 limit antiviral functions of NK cells

    Nature 2021; 600(7888):295-301.
  • Diefenbach, A.; Gnafakis, S.; Shomrat, O.

    Innate Lymphoid Cell-Epithelial Cell Modules Sustain Intestinal Homeostasis

    Immunity 2020; 52(3):452-463.
  • Schaupp, L.; Muth, S.; Rogell, L.; Kofoed-Branzk, M.; Melchior, F.; Lienenklaus, S.; Ganal-Vonarburg, S. C.; Klein, M.; Guendel, F.; Hain, T.; Schutze, K.; Grundmann, U.; Schmitt, V.; Dorsch, M.; Spanier, J.; Larsen, P. K.; Schwanz, T.; Jackel, S.; Reinhardt, C.; Bopp, T.; Danckwardt, S.; Mahnke, K.; Heinz, G. A.; Mashreghi, M. F.; Durek, P.; Kalinke, U.; Kretz, O.; Huber, T. B.; Weiss, S.; Wilhelm, C.; Macpherson, A. J.; Schild, H.; Diefenbach, A.; Probst, H. C.

    Microbiota-Induced Type I Interferons Instruct a Poised Basal State of Dendritic Cells

    Cell 2020; 181(5):1080-1096 e19.





Founded by the DFG (Project Number: 427826188)
Funding Period 2021-2024