Tissue-resident, extravascular Ly6c- monocytes are critical for inflammation in the synovium

Anna B Montgomery; Shang Yang Chen; Yidan Wang; Gaurav Gadhvi; Maximilian G Mayr; Carla M Cuda; Salina Dominguez; Hadijat-Kubura Moradeke Makinde; Miranda G Gurra; Alexander V Misharin; Arthur M Mandelin; Eric M Ruderman; Anjali Thakrar; Simran Brar; Mary Carns; Kathleen Aren; Mahzad Akbarpour; Andrew Filer; Saba Nayar; Ana Teososio; Triin Major; Ankit Bharat; G R Scott Budinger; Deborah R Winter; Harris Perlman

doi:10.1016/j.celrep.2023.112513

Tissue-resident, extravascular Ly6c- monocytes are critical for inflammation in the synovium

Anna B Montgomery, Shang Yang Chen, Yidan Wang, Gaurav Gadhvi, Maximilian G Mayr, Carla M Cuda, Salina Dominguez, Hadijat-Kubura Moradeke Makinde, Miranda G Gurra, Alexander V Misharin, Arthur M Mandelin, Eric M Ruderman, Anjali Thakrar, Simran Brar, Mary Carns, Kathleen Aren, Mahzad Akbarpour, Andrew Filer, Saba Nayar, Ana TeososioTriin Major, Ankit Bharat, G R Scott Budinger, Deborah R Winter^*, Harris Perlman^*

^*Corresponding author for this work

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

Abstract

Monocytes are abundant immune cells that infiltrate inflamed organs. However, the majority of monocyte studies focus on circulating cells, rather than those in tissue. Here, we identify and characterize an intravascular synovial monocyte population resembling circulating non-classical monocytes and an extravascular tissue-resident monocyte-lineage cell (TR-MC) population distinct in surface marker and transcriptional profile from circulating monocytes, dendritic cells, and tissue macrophages that are conserved in rheumatoid arthritis (RA) patients. TR-MCs are independent of NR4A1 and CCR2, long lived, and embryonically derived. TR-MCs undergo increased proliferation and reverse diapedesis dependent on LFA1 in response to arthrogenic stimuli and are required for the development of RA-like disease. Moreover, pathways that are activated in TR-MCs at the peak of arthritis overlap with those that are downregulated in LFA1-/- TR-MCs. These findings show a facet of mononuclear cell biology that could be imperative to understanding tissue-resident myeloid cell function in RA.

Original language	English
Article number	112513
Number of pages	25
Journal	Cell Reports
Volume	42
Issue number	5
Early online date	18 May 2023
DOIs	https://doi.org/10.1016/j.celrep.2023.112513
Publication status	Published - 30 May 2023

Bibliographical note

Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.

Acknowledgments
We would like to thank Dr. Steffen Jung for providing critical review of the manuscript. We would also like to thank the Northwestern University Lurie Cancer Center Flow Cytometry Core Facility, which is supported by NCI Cancer Center Support Grant P30 CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center; Dr. Hiam Abdala Valencia, Director of the Next Generation Sequencing Facility for the Divisions of Rheumatology/Pulmonary and Critical Care; the Northwestern NUSeq Core Facility; and Birmingham Tissue Analytics, University of Birmingham, UK. This research was supported in part through the computational resources and staff contributions provided by the Genomics Compute Cluster, which is jointly supported by the Feinberg School of Medicine, the Office of the Provost, the Office for Research, and Northwestern Information Technology. The Genomics Compute Cluster is part of Quest, Northwestern University’s high-performance computing facility, with the purpose to advance research in genomics. S.Y.C. was supported by a predoctoral AHA award (19PRE34380200). C.M.C. was supported by the Lupus Research Alliance (Novel Research Grant), the Rheumatology Research Foundation (Innovative Research Grant), and the Northwestern University Dixon Translational Research Initiative. H.-K.M.M. was supported by KL2 TR001424, HL134375S1, and AR007611. A.V.M. was supported by NIH grants U19AI135964, P01AG049665, PO1HL154998, R56HL135124, R01HL153312, and NUCATS COVID-19 Rapid Response Grant. A.B. was supported by NIH grants HL145478, HL147290, and HL147575. G.R.S.B. was supported by NIH grants U19AI135964, P01AG049665, P01AG04966506S1, and R01HL147575 and Veterans Affairs grant I01CX001777. D.R.W. was supported by funding from the Arthritis National Research Foundation, the American Federation for Aging Research, the American Heart Association (18CDA34110224), and NIH grants AI163742 and AR080513. H.P. was supported by AR074902, AR075423, CA060553, HL134375, AR080513, an RRF Innovative Research Grant, a United States-Israel Binational Science Foundation Investigator Grant, the Precision Medicine Fund, and the Mabel Green Myers Professorship.

Keywords

Humans
Monocytes/metabolism
Synovial Membrane
Arthritis, Rheumatoid
Inflammation/metabolism

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Cite this

Montgomery, A. B., Chen, S. Y., Wang, Y., Gadhvi, G., Mayr, M. G., Cuda, C. M., Dominguez, S., Moradeke Makinde, H.-K., Gurra, M. G., Misharin, A. V., Mandelin, A. M., Ruderman, E. M., Thakrar, A., Brar, S., Carns, M., Aren, K., Akbarpour, M., Filer, A., Nayar, S., ... Perlman, H. (2023). Tissue-resident, extravascular Ly6c- monocytes are critical for inflammation in the synovium. Cell Reports, 42(5), Article 112513. https://doi.org/10.1016/j.celrep.2023.112513

@article{71a40a1144344aa0bb26ad789b2c3cb7,

title = "Tissue-resident, extravascular Ly6c- monocytes are critical for inflammation in the synovium",

abstract = "Monocytes are abundant immune cells that infiltrate inflamed organs. However, the majority of monocyte studies focus on circulating cells, rather than those in tissue. Here, we identify and characterize an intravascular synovial monocyte population resembling circulating non-classical monocytes and an extravascular tissue-resident monocyte-lineage cell (TR-MC) population distinct in surface marker and transcriptional profile from circulating monocytes, dendritic cells, and tissue macrophages that are conserved in rheumatoid arthritis (RA) patients. TR-MCs are independent of NR4A1 and CCR2, long lived, and embryonically derived. TR-MCs undergo increased proliferation and reverse diapedesis dependent on LFA1 in response to arthrogenic stimuli and are required for the development of RA-like disease. Moreover, pathways that are activated in TR-MCs at the peak of arthritis overlap with those that are downregulated in LFA1-/- TR-MCs. These findings show a facet of mononuclear cell biology that could be imperative to understanding tissue-resident myeloid cell function in RA.",

keywords = "Humans, Monocytes/metabolism, Synovial Membrane, Arthritis, Rheumatoid, Inflammation/metabolism",

author = "Montgomery, {Anna B} and Chen, {Shang Yang} and Yidan Wang and Gaurav Gadhvi and Mayr, {Maximilian G} and Cuda, {Carla M} and Salina Dominguez and {Moradeke Makinde}, Hadijat-Kubura and Gurra, {Miranda G} and Misharin, {Alexander V} and Mandelin, {Arthur M} and Ruderman, {Eric M} and Anjali Thakrar and Simran Brar and Mary Carns and Kathleen Aren and Mahzad Akbarpour and Andrew Filer and Saba Nayar and Ana Teososio and Triin Major and Ankit Bharat and Budinger, {G R Scott} and Winter, {Deborah R} and Harris Perlman",

note = "Copyright {\textcopyright} 2023 The Authors. Published by Elsevier Inc. All rights reserved. Acknowledgments We would like to thank Dr. Steffen Jung for providing critical review of the manuscript. We would also like to thank the Northwestern University Lurie Cancer Center Flow Cytometry Core Facility, which is supported by NCI Cancer Center Support Grant P30 CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center; Dr. Hiam Abdala Valencia, Director of the Next Generation Sequencing Facility for the Divisions of Rheumatology/Pulmonary and Critical Care; the Northwestern NUSeq Core Facility; and Birmingham Tissue Analytics, University of Birmingham, UK. This research was supported in part through the computational resources and staff contributions provided by the Genomics Compute Cluster, which is jointly supported by the Feinberg School of Medicine, the Office of the Provost, the Office for Research, and Northwestern Information Technology. The Genomics Compute Cluster is part of Quest, Northwestern University{\textquoteright}s high-performance computing facility, with the purpose to advance research in genomics. S.Y.C. was supported by a predoctoral AHA award (19PRE34380200). C.M.C. was supported by the Lupus Research Alliance (Novel Research Grant), the Rheumatology Research Foundation (Innovative Research Grant), and the Northwestern University Dixon Translational Research Initiative. H.-K.M.M. was supported by KL2 TR001424, HL134375S1, and AR007611. A.V.M. was supported by NIH grants U19AI135964, P01AG049665, PO1HL154998, R56HL135124, R01HL153312, and NUCATS COVID-19 Rapid Response Grant. A.B. was supported by NIH grants HL145478, HL147290, and HL147575. G.R.S.B. was supported by NIH grants U19AI135964, P01AG049665, P01AG04966506S1, and R01HL147575 and Veterans Affairs grant I01CX001777. D.R.W. was supported by funding from the Arthritis National Research Foundation, the American Federation for Aging Research, the American Heart Association (18CDA34110224), and NIH grants AI163742 and AR080513. H.P. was supported by AR074902, AR075423, CA060553, HL134375, AR080513, an RRF Innovative Research Grant, a United States-Israel Binational Science Foundation Investigator Grant, the Precision Medicine Fund, and the Mabel Green Myers Professorship.",

year = "2023",

month = may,

day = "30",

doi = "10.1016/j.celrep.2023.112513",

language = "English",

volume = "42",

journal = "Cell Reports",

issn = "2211-1247",

publisher = "Elsevier",

number = "5",

}

Montgomery, AB, Chen, SY, Wang, Y, Gadhvi, G, Mayr, MG, Cuda, CM, Dominguez, S, Moradeke Makinde, H-K, Gurra, MG, Misharin, AV, Mandelin, AM, Ruderman, EM, Thakrar, A, Brar, S, Carns, M, Aren, K, Akbarpour, M, Filer, A , Nayar, S, Teososio, A, Major, T, Bharat, A, Budinger, GRS, Winter, DR & Perlman, H 2023, 'Tissue-resident, extravascular Ly6c- monocytes are critical for inflammation in the synovium', Cell Reports, vol. 42, no. 5, 112513. https://doi.org/10.1016/j.celrep.2023.112513

TY - JOUR

T1 - Tissue-resident, extravascular Ly6c- monocytes are critical for inflammation in the synovium

AU - Montgomery, Anna B

AU - Chen, Shang Yang

AU - Wang, Yidan

AU - Gadhvi, Gaurav

AU - Mayr, Maximilian G

AU - Cuda, Carla M

AU - Dominguez, Salina

AU - Moradeke Makinde, Hadijat-Kubura

AU - Gurra, Miranda G

AU - Misharin, Alexander V

AU - Mandelin, Arthur M

AU - Ruderman, Eric M

AU - Thakrar, Anjali

AU - Brar, Simran

AU - Carns, Mary

AU - Aren, Kathleen

AU - Akbarpour, Mahzad

AU - Filer, Andrew

AU - Nayar, Saba

AU - Teososio, Ana

AU - Major, Triin

AU - Bharat, Ankit

AU - Budinger, G R Scott

AU - Winter, Deborah R

AU - Perlman, Harris

N1 - Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved. Acknowledgments We would like to thank Dr. Steffen Jung for providing critical review of the manuscript. We would also like to thank the Northwestern University Lurie Cancer Center Flow Cytometry Core Facility, which is supported by NCI Cancer Center Support Grant P30 CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center; Dr. Hiam Abdala Valencia, Director of the Next Generation Sequencing Facility for the Divisions of Rheumatology/Pulmonary and Critical Care; the Northwestern NUSeq Core Facility; and Birmingham Tissue Analytics, University of Birmingham, UK. This research was supported in part through the computational resources and staff contributions provided by the Genomics Compute Cluster, which is jointly supported by the Feinberg School of Medicine, the Office of the Provost, the Office for Research, and Northwestern Information Technology. The Genomics Compute Cluster is part of Quest, Northwestern University’s high-performance computing facility, with the purpose to advance research in genomics. S.Y.C. was supported by a predoctoral AHA award (19PRE34380200). C.M.C. was supported by the Lupus Research Alliance (Novel Research Grant), the Rheumatology Research Foundation (Innovative Research Grant), and the Northwestern University Dixon Translational Research Initiative. H.-K.M.M. was supported by KL2 TR001424, HL134375S1, and AR007611. A.V.M. was supported by NIH grants U19AI135964, P01AG049665, PO1HL154998, R56HL135124, R01HL153312, and NUCATS COVID-19 Rapid Response Grant. A.B. was supported by NIH grants HL145478, HL147290, and HL147575. G.R.S.B. was supported by NIH grants U19AI135964, P01AG049665, P01AG04966506S1, and R01HL147575 and Veterans Affairs grant I01CX001777. D.R.W. was supported by funding from the Arthritis National Research Foundation, the American Federation for Aging Research, the American Heart Association (18CDA34110224), and NIH grants AI163742 and AR080513. H.P. was supported by AR074902, AR075423, CA060553, HL134375, AR080513, an RRF Innovative Research Grant, a United States-Israel Binational Science Foundation Investigator Grant, the Precision Medicine Fund, and the Mabel Green Myers Professorship.

PY - 2023/5/30

Y1 - 2023/5/30

N2 - Monocytes are abundant immune cells that infiltrate inflamed organs. However, the majority of monocyte studies focus on circulating cells, rather than those in tissue. Here, we identify and characterize an intravascular synovial monocyte population resembling circulating non-classical monocytes and an extravascular tissue-resident monocyte-lineage cell (TR-MC) population distinct in surface marker and transcriptional profile from circulating monocytes, dendritic cells, and tissue macrophages that are conserved in rheumatoid arthritis (RA) patients. TR-MCs are independent of NR4A1 and CCR2, long lived, and embryonically derived. TR-MCs undergo increased proliferation and reverse diapedesis dependent on LFA1 in response to arthrogenic stimuli and are required for the development of RA-like disease. Moreover, pathways that are activated in TR-MCs at the peak of arthritis overlap with those that are downregulated in LFA1-/- TR-MCs. These findings show a facet of mononuclear cell biology that could be imperative to understanding tissue-resident myeloid cell function in RA.

AB - Monocytes are abundant immune cells that infiltrate inflamed organs. However, the majority of monocyte studies focus on circulating cells, rather than those in tissue. Here, we identify and characterize an intravascular synovial monocyte population resembling circulating non-classical monocytes and an extravascular tissue-resident monocyte-lineage cell (TR-MC) population distinct in surface marker and transcriptional profile from circulating monocytes, dendritic cells, and tissue macrophages that are conserved in rheumatoid arthritis (RA) patients. TR-MCs are independent of NR4A1 and CCR2, long lived, and embryonically derived. TR-MCs undergo increased proliferation and reverse diapedesis dependent on LFA1 in response to arthrogenic stimuli and are required for the development of RA-like disease. Moreover, pathways that are activated in TR-MCs at the peak of arthritis overlap with those that are downregulated in LFA1-/- TR-MCs. These findings show a facet of mononuclear cell biology that could be imperative to understanding tissue-resident myeloid cell function in RA.

KW - Humans

KW - Monocytes/metabolism

KW - Synovial Membrane

KW - Arthritis, Rheumatoid

KW - Inflammation/metabolism

U2 - 10.1016/j.celrep.2023.112513

DO - 10.1016/j.celrep.2023.112513

M3 - Article

C2 - 37204925

SN - 2211-1247

VL - 42

JO - Cell Reports

JF - Cell Reports

IS - 5

M1 - 112513

ER -

Tissue-resident, extravascular Ly6c- monocytes are critical for inflammation in the synovium

Abstract

Bibliographical note

Keywords

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