Osteoimmunology

Resolution of inflammatory bone loss in autoimmune diseases

Head: Porf. Dr. rer. nat. Aline Bozec

The research focus of the Bozec Lab is to elucidate the cellular and molecular mechanisms that alter bone marrow in diseases such as rheumatoid arthritis, osteoporosis and cancer metastases. Using in vitro and in vivo loss and gain of function models, we have uncovered the important role of the immune system in the differentiation of bone cell types such as osteoclasts and osteoblasts.

Currently, we are describing the molecular mechanism by which

  •     altered transcription factors AP-1 and HIFs signaling in immune cells affect adaptive immunity, inflammation, and bone homeostasis, and
  •     elucidate the molecular link between bone osteocyte death and CLR-dependent myeloid cell activity.

 

  • The role of osteocyte cell death

We have already demonstrated that cellular debris released from osteocyte bone cells effectively stimulates bone resorption.
We are now trying to i) understand how osteocyte bone cells die, and ii) determine what drives increased bone resorption in fractures, osteonecrosis and arthritis.

  • Hypoxia-inducing factor-1a (HIF-1a), an oxygen sensor, appears to be a molecular switch of plasma cell homeostasis and inflammation.

We will investigate whether hypoxia induced in immune system B cells and intestinal plasma cells protects against infection. In the course of this, we will also analyze the role of hypoxia-induced changes in plasma cells in a fundamental aspect or during the immune response.

We have demonstrated that estrogen induces immune system B cells to enhance differentiation and function of bone resorbing cells. Next, we aim to describe the molecular mechanism of estrogen B cells that links autoimmune inflammation to bone loss.

  • The importance of ILC2-dependent resident versus induced eosinophils in the healing of inflammatory arthritis.

By combining an allergic disease model such as asthma with inflammatory arthritis, we have shown that a specific subset of eosinophils resolves arthritis. We now want to understand how to force this cell type to its resolving action.

  • The death of intestinal epithelial cells as a modulator of intestinal dysbiosis, systemic autoimmunity, and the development of arthritis

We have already found that hypoxic transcription factor proteins affect intestinal barrier function, which is impaired in experimental arthritis. Next, we want to demonstrate the link between hypoxia-induced death of the epithelium and arthritis.

 

Aline BozecResearch group leader
Bettina GrötschPostdoctoral researcher
Darja AndreevPostdoctoral researcher
Katerina KachlerPostdoctoral researcher
Xianyi MengPostdoctoral researcher
Christine ZechTechnical assistant
Franceska JelasTechnical assistant
Jule LindörferTechnical assistant
Sahar Asadi-AsadabadScientific doctoral student
Shazia AshrafScientific doctoral student
Shan CaoMedical doctoral student
Anastasia GaculenkoScientific doctoral student
Yewei JiaMedical doctoral student
Shobika Karuppusamy     Scientific doctoral student
Chaobo LaiMedical doctoral student
Nicolai LampertMedical doctoral student
Pang LyuMedical doctoral student
Elisabeth SchachtschabelMedical doctoral student
Rui SongMedical doctoral student
Estelle Tcheumi TactoumScientific doctoral student
Fulin ZhangMedical doctoral student
Wenshuo ZhangMedical doctoral student

 

Deutsche Forschungsgemeinschaft (DFG)
GRK 2740 "Bacterial infection induces HIF-1a that mediates glycolytic flux for IgA class switching." (2022-2027)

GRK 2599 "Hypoxia-inducible factor-1a (HIF-1a), a molecular switch controlling plasma cell homeostasis." (2020-2025)

CRC 1181 "The importance of ILC2 dependent resident versus induced eosinophils in the resolution of inflammatory arthritis." (2019-2023)

FOR 2886 - PANDORA "Cell death of intestinal epithelial cells as a modulator of intestinal dysbiosis, systemic autoimmunity and the development of arthritis" (2022-2025)

European Commission
ERC-Consolidator Grant "ODE - Unknown functions of Osteocyte DEath." (2021-2026)

IZKF, Universitätsklinikum Erlangen
A77 - "HIF expression in B cells regulates bone loss." (2020-2023)

 

  1. Meng X, Lin Z, Cao S, Janowska I, Sonomoto K, Andreev D, Katharina K, Wen J, Knaup KX, Wiesener MS, Krönke G, Rizzi M, Schett G, Bozec A. (2022) Estrogen-mediated downregulation of HIF-1α signaling in B lymphocytes influences postmenopausal bone loss. Bone Res. 10(1):15. IF:13.567
  2. Chen GL, Li R, Chen XX, Wang J, Cao S, Song R, Zhao MC, Li LM, Hannemmann N, Schett G, Qian C, Bozec A. (2021). Fra-2/AP-1 regulates melanoma cell metastasis by downregulating Fam212b. Cell Death Differ. 28(4):1364-1378. IF:15.83
  3. Andreev D, Liu M, Kachler K, Llerins Perez M, Kirchner P, Kölle J, Gießl A, Rauber S, Song R, Aust O, Grüneboom A, Kleyer A, Cañete JD, Ekici A, Ramming A, Finotto S, Schett G, Bozec A. (2020) Regulatory eosinophils induce the resolution of experimental arthritis and appear in remission state of human rheumatoid arthritis. Ann Rheum Dis. annrheumdis-2020-218902. IF:12.35
  4. Andreev D, Liu M, Weidner D, Kachler K, Faas M, Grüneboom A, Schlötzer-Schrehardt U, Muñoz LE, Steffen U, Grötsch B, Killy B, Krönke G, Luebke AM, Niemeier A, Wehrhan F, Lang R, Schett G, Bozec A. (2020) Osteocyte necrosis triggers osteoclast-mediated bone loss through macrophage-inducible C-type lectin. J Clin Invest. 130(9):4811-4830. IF:14.81
  5. Hannemann N, Cao S, Eriksson D, Schnelzer A, Jordan J, Eberhardt M, Schleicher U, Rech J, Ramming A, Uebe S, Ekici A, Cañete JD, Chen X, Bäuerle T, Vera J, Bogdan C, Schett G, Bozec A. (2019) Transcription factor Fra-1 targets Arginase-1 to enhance macrophage-mediated inflammation in arthritis. J Clin Invest. 129(7):2669-2684. IF:14.81
  6. Meng X, Grötsch B, Luo Y, Knaup KX, Wiesener MS, Chen XX, Jantsch J, Fillatreau S, Schett G, Bozec A. (2018) Hypoxia-inducible factor-1α is a critical transcription factor for IL-10-producing B cells in autoimmune disease. Nat Commun. 9(1):251. IF:14.92
  7. Ubieta K, Garcia M, Grötsch B, Uebe S, Weber GF, Stein M, Ekici A, Schett G, Mielenz D, Bozec A. (2017) Fra-2 regulates B cell development by enhancing IRF4 and Foxo1 transcription. J Exp Med. 214(7):2059-2071. IF:14.31
  8. Chen Z, Andreev D, Oeser K, Krljanac B, Hueber A, Kleyer A, Voehringer D, Schett G, Bozec A. (2016) Th2 and eosinophil responses suppress inflammatory arthritis. Nat Commun. 7:11596. IF:14.92
  9. Luo Y, Chen GL, Hannemann N, Ipseiz N, Krönke G, Bäuerle T, Munos L, Wirtz S, Schett G, Bozec A. (2015) Microbiota from obese mice regulate hematopoietic stem cell differentiation by altering the bone niche. Cell Metab. 22(5):886-94. IF:27.29
  10. Bozec A, Zaiss MM, Kagwiria R, Voll R, Rauh M, Chen Z, Mueller-Schmucker S, Kroczek RA, Heinzerling L, Moser M, Mellor AL, David JP, Schett G. (2014) T cell costimulation molecules CD80/86 inhibit osteoclast differentiation by inducing the IDO/tryptophan pathway. Sci Transl Med. 6(235):235ra60. IF:17.99

 

PubMed publication list of Prof. Dr. Aline Bozec

 

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