Head: Dr. rer. nat. D.Andreev
Research on the cellular and molecular mechanisms that trigger the resolution of inflammation and prevent pathological bone deterioration
The immune system is the human body's defense mechanism. It protects us from foreign substances and pathogens including helminths, bacteria and viruses. However, various genetic, epigenetic, and environmental factors can cause the immune system to malfunction, leading to autoimmune diseases like rheumatoid arthritis, where immune cells attack the body's own cells. These chronic conditions require patients to continuously adjust their medication and remain on it for a lifetime, posing significant health and economic burdens to both patients and society. Our research focuses on exploring potential cellular and molecular mechanisms that trigger the resolution of rheumatoid arthritis, with particular emphasis on type-2-related immune responses and the interaction between eosinophils and alternatively activated macrophages.
Another important aspect of our research is the investigation of cellular and molecular mechanisms that counteract pathological bone turnover as it is the case in postmenopausal osteoporosis and rheumatoid arthritis. Here we focus on the crosstalk between innate immune cells and bone cells including bone resorbing osteoclasts, bone forming osteoblasts and bone-resident osteocytes.
- Role of heme peroxidases as pro-resolving agents in inflammatory arthritis
The objective of this project is to uncover a novel immune regulatory function of heme peroxidases in rheumatoid arthritis. These peroxidases are produced in high amounts by granulocytes and can be found in arthritic joints. Traditionally, their role has been to generate reactive oxygen species (ROS) as a defense mechanism against invading pathogens. However, recent research suggests that heme peroxidases have a much more intricate role in the immune system, possessing not only pro-inflammatory properties but also various immune-modulatory effects.
The main focus of this project is to investigate how heme peroxidases may promote the transition of classical pro-inflammatory macrophages to alternatively activated macrophages with anti-inflammatory qualities, thereby facilitating the resolution of inflammatory arthritis.
- Regulatory functions of eosinophils during pathological bone remodeling
The equilibrium between bone formation by osteoblasts and bone resorption by osteoclasts is crucial for maintaining a healthy skeletal system. However, hormonal changes as during the menopause or inflammation, such as in rheumatoid arthritis, can disrupt this balance by enhancing the development of osteoclasts, which leads to low bone mass and an increased risk of fractures. While the pro-osteoclastogenic effects of immune cells and cytokines, such as TNFα, IL-1β, IL-6 and IL-17A have been extensively studied, the immune cells and mediators that inhibit osteoclast formation are not well understood.
Type-2-immunity-related cytokines, which are secreted in high amounts by eosinophils, have been found to suppress osteoclast differentiation and function. However, the regulatory role of eosinophils in bone health has been largely overlooked. Therefore, the objective of this project is to enhance or comprehension of how eosinophils regulate pathological bone decline as observed in postmenopausal osteoporosis and inflammatory arthritis and identify novel therapeutic approaches for these conditions.
|Darja Andreev||Junior Research group leader|
|Franceska Jelas||Technical assistant|
IZKF, Universitätsklinikum Erlangen
J90 - "The impact of eosinophils on bone loss." (2022-2024)
- Andreev D*, Kachler K*, Schett G, Bozec A. (2022). Rheumatoid arthritis and osteoimmunology: The adverse impact of a deregulated immune system on bone metabolism. Bone. 162:116468. doi: 10.1016/j.bone.2022.116468.
- Royzman D, Andreev D, Stich L, Peckert-Maier K, Wild AB, Zinser E, Mühl-Zürbes P, Jones E, Adam S, Frey S, Fuchs M, Kunz M, Bäuerle T, Nagel L, Schett G, Bozec A, Steinkasserer A. (2022). The soluble CD83 protein prevents bone destruction by inhibiting the formation of osteoclasts and inducing resolution of inflammation in arthritis. Front Immunol. 13:936995. doi: 10.3389/fimmu.2022.936995.
- Wen J, Lyu P, Stolzer I, Xu J, Gießl A, Lin Z, Andreev D, Kachler K, Song R, Meng X, Cao S, Guggino G, Ciccia F, Günther C, Schett G, Bozec A. (2022). Epithelial HIF2α expression induces intestinal barrier dysfunction and exacerbation of arthritis. Ann Rheum Dis. annrheumdis-2021-222035. doi: 10.1136/annrheumdis-2021-222035.
- 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. doi: 10.1038/s41413-022-00189-x.
- 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. 80(4):451-468. doi: 10.1136/annrheumdis-2020-218902.
- 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. doi:10.1172/JCI134214.
- Adam S, Simon N, Steffen U, Andes FT, Scholtysek C, Muller DIH, Weidner D, Andreev D, Kleyer A, Culemann S, Hahn M, Schett G, Kronke G, Frey S, Hueber AJ. (2020). JAK inhibition increases bone mass in steady-state conditions and ameliorates pathological bone loss by stimulating osteoblast function. Sci Transl Med. 12(530):eaay4447. doi: 10.1126/scitranslmed.aay4447.
- Grötsch B, Lux A, Rombouts Y, Hoffmann AC, Andreev D, Nimmerjahn F, Xiang W, Scherer HU, Schett G, Bozec A. (2019). Fra1 Controls Rheumatoid Factor Autoantibody Production by Bone Marrow Plasma Cells and the Development of Autoimmune Bone Loss. J Bone Miner Res. 34(7):1352-1365. doi: 10.1002/jbmr.3705.
- Omata Y, Frech M, Primbs T, Lucas S, Andreev D, Scholtysek C, Sarter K, Kindermann M, Yeremenko N, Baeten DL, Andreas N, Kamradt T, Bozec A, Ramming A, Krönke G, Wirtz S, Schett G, Zaiss MM. (2018). Group 2 Innate Lymphoid Cells Attenuate Inflammatory Arthritis and Protect from Bone Destruction in Mice. Cell Rep. 24(1):169-180. doi:10.1016/j.celrep.2018.06.005.
- 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. doi: 10.1038/ncomms11596.