CD200+ fibroblasts form a pro-resolving mesenchymal network in arthritis

Simon Rauber; Hashem Mohammadian; Christian Schmidkonz; Armin Atzinger; Alina Soare; Christoph Treutlein; Samuel Kemble; Christopher B. Mahony; Manuel Geisthoff; Mario R. Angeli; Maria G. Raimondo; Cong Xu; Kai-Ting Yang; Le Lu; Hannah Labinsky; Mina S. A. Saad; Charles A. Gwellem; Jiyang Chang; Kaiyue Huang; Eleni Kampylafka; Johannes Knitza; Rostyslav Bilyy; Jörg H. W. Distler; Megan M. Hanlon; Ursula Fearon; Douglas J. Veale; Frank W. Roemer; Tobias Bäuerle; Hans M. Maric; Simone Maschauer; Arif B. Ekici; Christopher D. Buckley; Adam P. Croft; Torsten Kuwert; Olaf Prante; Juan D. Cañete; Georg Schett; Andreas Ramming

doi:10.1038/s41590-024-01774-4

CD200⁺ fibroblasts form a pro-resolving mesenchymal network in arthritis

Simon Rauber, Hashem Mohammadian, Christian Schmidkonz, Armin Atzinger, Alina Soare, Christoph Treutlein, Samuel Kemble, Christopher B. Mahony, Manuel Geisthoff, Mario R. Angeli, Maria G. Raimondo, Cong Xu, Kai-Ting Yang, Le Lu, Hannah Labinsky, Mina S. A. Saad, Charles A. Gwellem, Jiyang Chang, Kaiyue Huang, Eleni KampylafkaJohannes Knitza, Rostyslav Bilyy, Jörg H. W. Distler, Megan M. Hanlon, Ursula Fearon, Douglas J. Veale, Frank W. Roemer, Tobias Bäuerle, Hans M. Maric, Simone Maschauer, Arif B. Ekici, Christopher D. Buckley, Adam P. Croft, Torsten Kuwert, Olaf Prante, Juan D. Cañete, Georg Schett, Andreas Ramming^*

^*Corresponding author for this work

Inflammation and Ageing

Research output: Contribution to journal › Article › peer-review

Abstract

Fibroblasts are important regulators of inflammation, but whether fibroblasts change phenotype during resolution of inflammation is not clear. Here we use positron emission tomography to detect fibroblast activation protein (FAP) as a means to visualize fibroblast activation in vivo during inflammation in humans. While tracer accumulation is high in active arthritis, it decreases after tumor necrosis factor and interleukin-17A inhibition. Biopsy-based single-cell RNA-sequencing analyses in experimental arthritis show that FAP signal reduction reflects a phenotypic switch from pro-inflammatory MMP3⁺/IL6⁺ fibroblasts (high FAP internalization) to pro-resolving CD200⁺DKK3⁺ fibroblasts (low FAP internalization). Spatial transcriptomics of human joints indicates that pro-resolving niches of CD200⁺DKK3⁺ fibroblasts cluster with type 2 innate lymphoid cells, whereas MMP3⁺/IL6⁺ fibroblasts colocalize with inflammatory immune cells. CD200⁺DKK3⁺ fibroblasts stabilized the type 2 innate lymphoid cell phenotype and induced resolution of arthritis via CD200–CD200R1 signaling. Taken together, these data suggest a dynamic molecular regulation of the mesenchymal compartment during resolution of inflammation.

Original language	English
Journal	Nature Immunology
Early online date	23 Feb 2024
DOIs	https://doi.org/10.1038/s41590-024-01774-4
Publication status	E-pub ahead of print - 23 Feb 2024

Bibliographical note

Acknowledgments:
We thank M. Rose, C. Pfaff, J. Tu and V. Fedorchenko for excellent technical assistance. We thank U. Appelt and M. Mroz from the FAU ‘Core Unit für Zellsortierung und Immunomonitoring’ for cell sorting. We acknowledge the FAU NGS core facility for sequencing. We acknowledge S. Bauer, C. Renner (both former scientists of UZH Zurich, Switzerland) and U. Haberkorn (Department of Nuclear Medicine, University Hospital Heidelberg, Germany) for supplying the HT1080-FAP transfected cell line. We acknowledge iTheranostics, a Delaware corporation, for providing the FAPI-04 precursor. We acknowledge W. Baum (Department of Medicine 3, University Hospital Erlangen, Germany) for providing K/BxN serum. The work was supported by the German Research Foundation (DFG) to A.R. (RA 2506/4-1, RA 2506/4-2, RA 2506/6-1, RA 2506/7-1), to M.G.R. (Clinician Scientist Program NOTICE), to A.S. (SO 1735/2-1) and to G.S. (SCHE 1583/7-1); CRC1181 to G.S. (projects A01/Z03) and A.R. (project C06); CRC/TRR 369 DIONE to G.S. and A.R.; Gottfried Wilhelm Leibniz Prize 2023 to G.S. The work was supported by the European Research Council (853508 BARRIER BREAK) to A.R. and EC project Nanoscope 4D to G.S. The work was supported by the Federal Ministry of Education and Research (BMBF) to T.K., G.S. and A.R. (MASCARA). This work was supported by the Innovative Medicines Initiative projects RTCure and HIPPOCRATES to G.S. and A.R. The work was supported by Novartis Pharma to A.R. The work was supported by the Interdisciplinary Centre for Clinical Research (IZKF) Erlangen (D034 to A.R., P049 and J106 to M.G.R., J107 to S.R.). The present work was performed in partial fulfillment of the requirements for obtaining the degree rer. biol. hum. at the FAU Erlangen-Nürnberg.

© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.

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Cite this

Rauber, S., Mohammadian, H., Schmidkonz, C., Atzinger, A., Soare, A., Treutlein, C., Kemble, S., Mahony, C. B., Geisthoff, M., Angeli, M. R., Raimondo, M. G., Xu, C., Yang, K.-T., Lu, L., Labinsky, H., Saad, M. S. A., Gwellem, C. A., Chang, J., Huang, K., ... Ramming, A. (2024). CD200⁺ fibroblasts form a pro-resolving mesenchymal network in arthritis. Nature Immunology. Advance online publication. https://doi.org/10.1038/s41590-024-01774-4

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title = "CD200+ fibroblasts form a pro-resolving mesenchymal network in arthritis",

abstract = "Fibroblasts are important regulators of inflammation, but whether fibroblasts change phenotype during resolution of inflammation is not clear. Here we use positron emission tomography to detect fibroblast activation protein (FAP) as a means to visualize fibroblast activation in vivo during inflammation in humans. While tracer accumulation is high in active arthritis, it decreases after tumor necrosis factor and interleukin-17A inhibition. Biopsy-based single-cell RNA-sequencing analyses in experimental arthritis show that FAP signal reduction reflects a phenotypic switch from pro-inflammatory MMP3+/IL6+ fibroblasts (high FAP internalization) to pro-resolving CD200+DKK3+ fibroblasts (low FAP internalization). Spatial transcriptomics of human joints indicates that pro-resolving niches of CD200+DKK3+ fibroblasts cluster with type 2 innate lymphoid cells, whereas MMP3+/IL6+ fibroblasts colocalize with inflammatory immune cells. CD200+DKK3+ fibroblasts stabilized the type 2 innate lymphoid cell phenotype and induced resolution of arthritis via CD200–CD200R1 signaling. Taken together, these data suggest a dynamic molecular regulation of the mesenchymal compartment during resolution of inflammation. ",

author = "Simon Rauber and Hashem Mohammadian and Christian Schmidkonz and Armin Atzinger and Alina Soare and Christoph Treutlein and Samuel Kemble and Mahony, {Christopher B.} and Manuel Geisthoff and Angeli, {Mario R.} and Raimondo, {Maria G.} and Cong Xu and Kai-Ting Yang and Le Lu and Hannah Labinsky and Saad, {Mina S. A.} and Gwellem, {Charles A.} and Jiyang Chang and Kaiyue Huang and Eleni Kampylafka and Johannes Knitza and Rostyslav Bilyy and Distler, {J{\"o}rg H. W.} and Hanlon, {Megan M.} and Ursula Fearon and Veale, {Douglas J.} and Roemer, {Frank W.} and Tobias B{\"a}uerle and Maric, {Hans M.} and Simone Maschauer and Ekici, {Arif B.} and Buckley, {Christopher D.} and Croft, {Adam P.} and Torsten Kuwert and Olaf Prante and Ca{\~n}ete, {Juan D.} and Georg Schett and Andreas Ramming",

note = "Acknowledgments: We thank M. Rose, C. Pfaff, J. Tu and V. Fedorchenko for excellent technical assistance. We thank U. Appelt and M. Mroz from the FAU {\textquoteleft}Core Unit f{\"u}r Zellsortierung und Immunomonitoring{\textquoteright} for cell sorting. We acknowledge the FAU NGS core facility for sequencing. We acknowledge S. Bauer, C. Renner (both former scientists of UZH Zurich, Switzerland) and U. Haberkorn (Department of Nuclear Medicine, University Hospital Heidelberg, Germany) for supplying the HT1080-FAP transfected cell line. We acknowledge iTheranostics, a Delaware corporation, for providing the FAPI-04 precursor. We acknowledge W. Baum (Department of Medicine 3, University Hospital Erlangen, Germany) for providing K/BxN serum. The work was supported by the German Research Foundation (DFG) to A.R. (RA 2506/4-1, RA 2506/4-2, RA 2506/6-1, RA 2506/7-1), to M.G.R. (Clinician Scientist Program NOTICE), to A.S. (SO 1735/2-1) and to G.S. (SCHE 1583/7-1); CRC1181 to G.S. (projects A01/Z03) and A.R. (project C06); CRC/TRR 369 DIONE to G.S. and A.R.; Gottfried Wilhelm Leibniz Prize 2023 to G.S. The work was supported by the European Research Council (853508 BARRIER BREAK) to A.R. and EC project Nanoscope 4D to G.S. The work was supported by the Federal Ministry of Education and Research (BMBF) to T.K., G.S. and A.R. (MASCARA). This work was supported by the Innovative Medicines Initiative projects RTCure and HIPPOCRATES to G.S. and A.R. The work was supported by Novartis Pharma to A.R. The work was supported by the Interdisciplinary Centre for Clinical Research (IZKF) Erlangen (D034 to A.R., P049 and J106 to M.G.R., J107 to S.R.). The present work was performed in partial fulfillment of the requirements for obtaining the degree rer. biol. hum. at the FAU Erlangen-N{\"u}rnberg. {\textcopyright} 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.",

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doi = "10.1038/s41590-024-01774-4",

language = "English",

journal = "Nature Immunology",

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Rauber, S, Mohammadian, H, Schmidkonz, C, Atzinger, A, Soare, A, Treutlein, C, Kemble, S , Mahony, CB, Geisthoff, M, Angeli, MR, Raimondo, MG, Xu, C, Yang, K-T, Lu, L, Labinsky, H, Saad, MSA, Gwellem, CA, Chang, J, Huang, K, Kampylafka, E, Knitza, J, Bilyy, R, Distler, JHW, Hanlon, MM, Fearon, U, Veale, DJ, Roemer, FW, Bäuerle, T, Maric, HM, Maschauer, S, Ekici, AB, Buckley, CD, Croft, AP, Kuwert, T, Prante, O, Cañete, JD, Schett, G & Ramming, A 2024, 'CD200⁺ fibroblasts form a pro-resolving mesenchymal network in arthritis', Nature Immunology. https://doi.org/10.1038/s41590-024-01774-4

TY - JOUR

T1 - CD200+ fibroblasts form a pro-resolving mesenchymal network in arthritis

AU - Rauber, Simon

AU - Mohammadian, Hashem

AU - Schmidkonz, Christian

AU - Atzinger, Armin

AU - Soare, Alina

AU - Treutlein, Christoph

AU - Kemble, Samuel

AU - Mahony, Christopher B.

AU - Geisthoff, Manuel

AU - Angeli, Mario R.

AU - Raimondo, Maria G.

AU - Xu, Cong

AU - Yang, Kai-Ting

AU - Lu, Le

AU - Labinsky, Hannah

AU - Saad, Mina S. A.

AU - Gwellem, Charles A.

AU - Chang, Jiyang

AU - Huang, Kaiyue

AU - Kampylafka, Eleni

AU - Knitza, Johannes

AU - Bilyy, Rostyslav

AU - Distler, Jörg H. W.

AU - Hanlon, Megan M.

AU - Fearon, Ursula

AU - Veale, Douglas J.

AU - Roemer, Frank W.

AU - Bäuerle, Tobias

AU - Maric, Hans M.

AU - Maschauer, Simone

AU - Ekici, Arif B.

AU - Buckley, Christopher D.

AU - Croft, Adam P.

AU - Kuwert, Torsten

AU - Prante, Olaf

AU - Cañete, Juan D.

AU - Schett, Georg

AU - Ramming, Andreas

N1 - Acknowledgments: We thank M. Rose, C. Pfaff, J. Tu and V. Fedorchenko for excellent technical assistance. We thank U. Appelt and M. Mroz from the FAU ‘Core Unit für Zellsortierung und Immunomonitoring’ for cell sorting. We acknowledge the FAU NGS core facility for sequencing. We acknowledge S. Bauer, C. Renner (both former scientists of UZH Zurich, Switzerland) and U. Haberkorn (Department of Nuclear Medicine, University Hospital Heidelberg, Germany) for supplying the HT1080-FAP transfected cell line. We acknowledge iTheranostics, a Delaware corporation, for providing the FAPI-04 precursor. We acknowledge W. Baum (Department of Medicine 3, University Hospital Erlangen, Germany) for providing K/BxN serum. The work was supported by the German Research Foundation (DFG) to A.R. (RA 2506/4-1, RA 2506/4-2, RA 2506/6-1, RA 2506/7-1), to M.G.R. (Clinician Scientist Program NOTICE), to A.S. (SO 1735/2-1) and to G.S. (SCHE 1583/7-1); CRC1181 to G.S. (projects A01/Z03) and A.R. (project C06); CRC/TRR 369 DIONE to G.S. and A.R.; Gottfried Wilhelm Leibniz Prize 2023 to G.S. The work was supported by the European Research Council (853508 BARRIER BREAK) to A.R. and EC project Nanoscope 4D to G.S. The work was supported by the Federal Ministry of Education and Research (BMBF) to T.K., G.S. and A.R. (MASCARA). This work was supported by the Innovative Medicines Initiative projects RTCure and HIPPOCRATES to G.S. and A.R. The work was supported by Novartis Pharma to A.R. The work was supported by the Interdisciplinary Centre for Clinical Research (IZKF) Erlangen (D034 to A.R., P049 and J106 to M.G.R., J107 to S.R.). The present work was performed in partial fulfillment of the requirements for obtaining the degree rer. biol. hum. at the FAU Erlangen-Nürnberg. © 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.

PY - 2024/2/23

Y1 - 2024/2/23

N2 - Fibroblasts are important regulators of inflammation, but whether fibroblasts change phenotype during resolution of inflammation is not clear. Here we use positron emission tomography to detect fibroblast activation protein (FAP) as a means to visualize fibroblast activation in vivo during inflammation in humans. While tracer accumulation is high in active arthritis, it decreases after tumor necrosis factor and interleukin-17A inhibition. Biopsy-based single-cell RNA-sequencing analyses in experimental arthritis show that FAP signal reduction reflects a phenotypic switch from pro-inflammatory MMP3+/IL6+ fibroblasts (high FAP internalization) to pro-resolving CD200+DKK3+ fibroblasts (low FAP internalization). Spatial transcriptomics of human joints indicates that pro-resolving niches of CD200+DKK3+ fibroblasts cluster with type 2 innate lymphoid cells, whereas MMP3+/IL6+ fibroblasts colocalize with inflammatory immune cells. CD200+DKK3+ fibroblasts stabilized the type 2 innate lymphoid cell phenotype and induced resolution of arthritis via CD200–CD200R1 signaling. Taken together, these data suggest a dynamic molecular regulation of the mesenchymal compartment during resolution of inflammation.

AB - Fibroblasts are important regulators of inflammation, but whether fibroblasts change phenotype during resolution of inflammation is not clear. Here we use positron emission tomography to detect fibroblast activation protein (FAP) as a means to visualize fibroblast activation in vivo during inflammation in humans. While tracer accumulation is high in active arthritis, it decreases after tumor necrosis factor and interleukin-17A inhibition. Biopsy-based single-cell RNA-sequencing analyses in experimental arthritis show that FAP signal reduction reflects a phenotypic switch from pro-inflammatory MMP3+/IL6+ fibroblasts (high FAP internalization) to pro-resolving CD200+DKK3+ fibroblasts (low FAP internalization). Spatial transcriptomics of human joints indicates that pro-resolving niches of CD200+DKK3+ fibroblasts cluster with type 2 innate lymphoid cells, whereas MMP3+/IL6+ fibroblasts colocalize with inflammatory immune cells. CD200+DKK3+ fibroblasts stabilized the type 2 innate lymphoid cell phenotype and induced resolution of arthritis via CD200–CD200R1 signaling. Taken together, these data suggest a dynamic molecular regulation of the mesenchymal compartment during resolution of inflammation.

U2 - 10.1038/s41590-024-01774-4

DO - 10.1038/s41590-024-01774-4

M3 - Article

C2 - 38396288

SN - 1529-2908

JO - Nature Immunology

JF - Nature Immunology

ER -