Novel Insights into the Ontogenetic and Functional Heterogeneity of
                    Macrophages in Synovial Tissue and Bone

Gulce Itir Percin; Anika Grüneboom; Claudia Waskow; Stephan Culemann

doi:10.1055/a-1650-9195

Osteologie 2021; 30(04): 292-298
DOI: 10.1055/a-1650-9195

Review

Novel Insights into the Ontogenetic and Functional Heterogeneity of Macrophages in Synovial Tissue and Bone

Neue Erkenntnisse über die ontogenetische und funktionelle Heterogenität von Makrophagen in synovialem Gewebe und Knochen

Gulce Itir Percin

¹Immunologie des Alterns, Leibniz Institut für Altersforschung – Fritz-Lipmann Institut eV, Jena, Germany

,

Anika Grüneboom

²Biospektroskopie, Leibniz-Institut für Analytische Wissenschaften – ISAS eV, Dortmund, Germany

³Medizinische Fakultät, Universitätsklinikum Essen, Essen, Germany

,

Claudia Waskow

¹Immunologie des Alterns, Leibniz Institut für Altersforschung – Fritz-Lipmann Institut eV, Jena, Germany

⁴Department of Medicine III, Technical University Dresden, Dresden, Germany

⁵Institut für Biochemie und Biophysik, Fakultät für Biowissenschaften, Friedrich-Schiller-Universitat Jena, Jena, Germany

,

Stephan Culemann

¹Immunologie des Alterns, Leibniz Institut für Altersforschung – Fritz-Lipmann Institut eV, Jena, Germany

› Author Affiliations

Abstract

Inflammatory joint diseases like rheumatoid arthritis (RA) belong to the most prevalent autoimmune disorders. RA is characterized by a massive infiltration of immune cells into synovial tissue, cartilage destruction and bone erosion. The perpetuating inflammatory and destructive milieu is associated with severe pain and culminates in complete disability of synovial joints. The events initiating RA are still not fully understood and the treatments are mainly confined to strategies that modify and inhibit the body’s immune system. Macrophages and osteoclasts (OC) are myeloid cells of the innate immune system and are considered to play a central role in the inflammatory and destructive events of arthritis by production of inflammatory cytokines and mediating pathological bone resorption. In recent years, the use of novel fate mapping strategies identifying the origin and cellular development (ontogeny) of OC and macrophages in conjunction with new genetically modified mouse models, single cell analysis and advanced imaging techniques substantially changed our understanding on the ontogenetic and functional heterogeneity of these cells.

Zusammenfassung

Entzündliche Gelenkerkrankungen wie rheumatoide Arthritis (RA) gehören zu den häufigsten Autoimmunerkrankungen. RA ist durch eine massive Infiltration von Immunzellen in das Synovialgewebe, Knorpelzerstörung und Knochenerosion charakterisiert. Ein andauerndes entzündliches und destruktives Milieu geht mit starken Schmerzen einher und endet schließlich mit vollständigem Funktionsverlust der Gelenke. Die initialen Ereignisse der RA sind immer noch nicht vollständig verstanden und Behandlungen beschränken sich weitestgehend auf Strategien, welche das körpereigene Immunsystem hemmen. Makrophagen und Osteoklasten sind myeloide Zellen, die zum angeborenen Immunsystem gehören. Durch die Produktion von entzündungsfördernden Zytokinen und krankhafter Knochenresorption wird ihnen eine zentrale Rolle bei den entzündlichen und destruktiven Mechanismen der Arthritis zugeschrieben. Mithilfe neuester fate mapping-Strategien, welche den Ursprung und die zelluläre Entwicklung (Ontogenese) von Makrophagen und Osteoklasten identifizierten, sowie innovativer genetisch-modifizierter Mausmodelle, Einzelzell-Analysen und fortschrittlicher Bildgebungstechnik wurde unser Verständnis über die ontogenetische und funktionelle Heterogenität in den vergangenen Jahren substantiell erweitert.

Full Text

References

References
1 Kaufmann SHE. Immunology’s foundation: the 100-year anniversary of the Nobel Prize to Paul Ehrlich and Elie Metchnikoff. Nat Immunol 2008; 9: 705-712
2 Okabe Y, Medzhitov R. Tissue biology perspective on macrophages. Nat Immunol 2016; 17: 9-17
3 van Furth R, Cohn ZA. The origin and kinetics of mononuclear phagocytes. J Exp Med 1968; 415-435
4 Shaw TN, Houston SA, Wemyss K. et al Tissue-resident macrophages in the intestine are long lived and defined by Tim-4 and CD4 expression. J Exp Med 2018; 215: 1507-1518
5 Perdiguero EG, Geissmann F. The development and maintenance of resident macrophages. Nat Immunol 2016; 17: 2-8
6 Ginhoux F, Schultze JL, Murray PJ. et al New insights into the multidimensional concept of macrophage ontogeny, activation and function. Nat Immunol 2016; 17: 34-40
7 Parkhurst CN, Yang G, Ninan I. et al Microglia Promote Learning-Dependent Synapse Formation through Brain-Derived Neurotrophic Factor. Cell 2013; 155: 1596-1609
8 Ruder B, Becker C. At the Forefront of the Mucosal Barrier: The Role of Macrophages in the Intestine. Cells 2020; 9: 2162
9 Trapnell BC, Whitsett JA. GM-CSF Regulates Pulmonary Surfactant Homeostasis and Alveolar Macrophage-Mediated Innate Host Defense. Annu Rev Physiol 2002; 64: 775-802
10 Kohyama M, Ise W, Edelson BT. et al Critical role for Spi-C in the development of red pulp macrophages and splenic iron homeostasis. 2009 10.
11 Ginhoux F, Jung S. Monocytes and macrophages: developmental pathways and tissue homeostasis. Nat Rev Immunol 2014; 14: 392-404
12 Culemann S, Grüneboom A, Nicolás-Ávila JÁ. et al Locally renewing resident synovial macrophages provide a protective barrier for the joint. Nature 2019; 572: 670-675
13 Udalova IA, Mantovani A, Feldmann M. Macrophage heterogeneity in the context of rheumatoid arthritis. Nat Rev Rheumatol 2016; 12: 472-485
14 Culemann S, Grüneboom A, Krönke G. Origin and function of synovial macrophage subsets during inflammatory joint disease. Adv Immunol 2019; 143: 75-98
15 Chu CQ, Field M, Feldmann M. et al Localization of Tumor Necrosis Factor α in Synovial Tissues and at the Cartilage–Pannus Junction in Patients With Rheumatoid Arthritis. Arthritis Rheum 1991; 34: 1125-1132
16 Accelerating Medicines Partnership Rheumatoid Arthritis and Systemic Lupus Erythematosus (AMP RA/SLE) Consortium . Zhang F, Wei K. et al Defining inflammatory cell states in rheumatoid arthritis joint synovial tissues by integrating single-cell transcriptomics and mass cytometry. Nat Immunol 2019; 20: 928-942
17 Kuo D, Ding J, Cohn IS. et al HBEGF+macrophages in rheumatoid arthritis induce fibroblast invasiveness. Sci Transl Med 2019; 11: eaau8587
18 Geddes PAC. The Origin of the Osteoblast and of the Osteoclast. A Anat Physiol 1913; 47: 159-176
19 Jacome-Galarza CE, Lee S-K, Lorenzo JA. et al Identification, characterization, and isolation of a common progenitor for osteoclasts, macrophages, and dendritic cells from murine bone marrow and periphery. J Bone Miner Res 2013; 28: 1203-1213
20 Grigoriadis AE, Wang Z-Q, Cecchini MG. et al c-Fos: A Key Regulator of Osteoclast-Macrophage Lineage Determination and Bone Remodeling. Sci New Ser 1994; 266: 443-448
21 Jacome-Galarza CE, Percin GI, Muller JT. et al Developmental origin, functional maintenance and genetic rescue of osteoclasts. Nature 2019; 568: 541-545
22 Jansen IDC, Vermeer JAF, Bloemen V. et al Osteoclast Fusion and Fission. Calcif Tissue Int 2012; 90: 515-522
23 Walker DG. Congenital Osteopetrosis in Mice Cured by Parabiotic Union with Normal Siblings. Endocrinology 1972; 91: 916-920
24 Steffen U, Schett G, Bozec A. How Autoantibodies Regulate Osteoclast Induced Bone Loss in Rheumatoid Arthritis. Front Immunol 2019; 10: 1483
25 Hasegawa T, Kikuta J, Sudo T. et al Identification of a novel arthritis-associated osteoclast precursor macrophage regulated by FoxM1. Nat Immunol 2019; 20: 1631-1643
26 Xue J, Xu L, Zhu H. et al CD14+CD16− monocytes are the main precursors of osteoclasts in rheumatoid arthritis via expressing Tyro3TK. Arthritis Res Ther 2020; 22: 221
27 Wakkach A, Mansour A, Dacquin R. et al Bone marrow microenvironment controls the in vivo differentiation of murine dendritic cells into osteoclasts. Blood 2008; 112: 5074-5083
28 Narisawa M, Kubo S, Okada Y. et al Human dendritic cell-derived osteoclasts with high bone resorption capacity and T cell stimulation ability. Bone 2021; 142: 115616
29 Grüneboom A, Hawwari I, Weidner D. et al A network of trans-cortical capillaries as mainstay for blood circulation in long bones. Nat Metab 2019; 1: 236-250
30 Romeo SG, Alawi KM, Rodrigues J. et al Endothelial proteolytic activity and interaction with non-resorbing osteoclasts mediate bone elongation. Nat Cell Biol 2019; 21: 430-441
31 Hashimoto K, Kaito T, Kikuta J. et al Intravital imaging of orthotopic and ectopic bone. Inflamm Regen 2020; 40: 26
32 Hasegawa T, Kikuta J, Ishii M. Imaging the Bone-Immune Cell Interaction in Bone Destruction. Front Immunol 2019; 10: 596
33 Hasegawa T, Kikuta J, Sudo T. et al Development of an intravital imaging system for the synovial tissue reveals the dynamics of CTLA-4 Ig in vivo. Sci Rep 2020; 10: 13480
34 Ishii M, Egen JG, Klauschen F. et al Sphingosine-1-phosphate mobilizes osteoclast precursors and regulates bone homeostasis. Nature 2009; 458: 524-528
35 McDonald MM, Khoo WH, Ng PY. et al Osteoclasts recycle via osteomorphs during RANKL-stimulated bone resorption. Cell 2021; 184: 1330-1347.e13
36 Grüneboom A, Kling L, Christiansen S. et al Next-generation imaging of the skeletal system and its blood supply. Nat Rev Rheumatol 2019; 15: 533-549