The Selective Expansion and Targeted Accumulation of Bone Marrow–Derived Macrophages Drive Cardiac Vasculitis

Stock, Angus T.; Collins, Nicholas; Smyth, Gordon K.; Hu, Yifang; Hansen, Jacinta; D'Silva, Damian B; Jama, Hamdi; Lew, Andrew M.; Gebhardt, Thomas; McLean, Catriona; Wicks, Ian P.

doi:10.4049/jimmunol.1900071

Cited by 11 publications

(14 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Historical dogma holds that monocyte‐derived tissue macrophages have been proven to only partially represent the entire spectrum of macrophages found in tissues 54 . Recently, LYVE1‐expressing macrophages were characterized as tissue‐resident macrophages in multiple organs including heart, adipose tissue, and placenta, and were located close to vessels 55‐60 . Silva at al.…”

Section: Discussionmentioning

confidence: 99%

Single‐cell RNA sequencing reveals the induction of novel myeloid and myeloid‐associated cell populations in visceral fat with long‐term obesity

et al. 2021

View full text Add to dashboard Cite

Macrophages and other immune cells are important contributors to obesity‐associated inflammation; however, the cellular identities of these specific populations remain unknown. In this study, we identified individual populations of myeloid cells found in mouse epididymal/visceral adipose tissue by single‐cell RNA sequencing, immunofluorescence, and flow cytometry. Multiple canonical correlation analysis identified 11 unique myeloid and myeloid‐associate cell populations. In obese mice, we detected an increased percentage of monocyte‐derived pro‐inflammatory cells expressing Cd9 and Trem2, as well as significantly decreased percentages of multiple cell populations, including tissue‐resident cells expressing Lyve1, Mafb, and Mrc1. We have identified and validated a novel myeloid/macrophage population defined by Ly6a expression, exhibiting both myeloid and mesenchymal characteristics, which increased with obesity and showed high pro‐fibrotic characteristics in vitro. Our mouse adipose tissue myeloid cell atlas provides an important resource to investigate obesity‐associated inflammation and fibrosis.

show abstract

Section: Discussionmentioning

confidence: 99%

Single‐cell RNA sequencing reveals the induction of novel myeloid and myeloid‐associated cell populations in visceral fat with long‐term obesity

et al. 2021

View full text Add to dashboard Cite

show abstract

“…While supported by a range of known marker genes, our results require confirmation in a larger patient cohort before generalisation. Nevertheless, given the well-known role of monocytes in KD animal models [5,8] and cardiac inflammation and repair [15] the changes we observe are likely to be highly relevant. Measuring monocyte subsets could stratify PIMS-TS and KD patients and predict disease resistance.…”

Section: Mainmentioning

confidence: 93%

“…This risk is significantly reduced with early treatment using intravenous immunoglobulin (IVIG) although 20% of patients require additional interventions due to failure to respond to initial treatment [6]. The immunology of KD is still not fully understood but patient data and animal models suggest monocytes are involved [5,7,8]. The CAWS mouse model of KD shows increased recruitment and accumulation of bone marrow derived monocytes into the heart and the inflammatory cytokine IL1-beta are both essential for pathogenesis [8].…”

Section: Mainmentioning

confidence: 99%

“…While supported by a range of known marker genes, our results require confirmation in a larger patient cohort before generalisation. Nevertheless, given the well-known role of monocytes in KD animal models [5,8] is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint…”

Section: Mainmentioning

confidence: 99%

“…The immunology of KD is still not fully understood but patient data and animal models suggest monocytes are involved [5,7,8]. The CAWS mouse model of KD shows increased recruitment and accumulation of bone marrow derived monocytes into the heart and the inflammatory cytokine IL1-beta are both essential for pathogenesis [8]. Given the recent emergence of PIMS-TS, little is known about the immunological processes driving the disease and whether these are similar or different to KD.…”

Section: Mainmentioning

confidence: 99%

See 2 more Smart Citations

The innate and adaptive immune landscape of SARS-CoV-2-associated Multisystem Inflammatory Syndrome in Children (MIS-C) from acute disease to recovery

Syrimi

Fennell

Richter

et al. 2020

Preprint

View full text Add to dashboard Cite

Paediatric inflammatory multisystem inflammatory syndrome temporally associated with SARS-CoV-2 infection (PIMS-TS) is a new disease with overlapping features of Kawasaki disease (KD) and toxic shock syndrome. Unbiased single cell RNA sequencing analysis of peripheral blood mononuclear cells from PIMS-TS and KD patients shows monocytes are the main source of pro-inflammatory cytokines and large changes in the frequency of classical, intermediate and non-classical monocytes occur in both diseases.

show abstract

Mechanistic Target of Rapamycin Inhibition Prevents Coronary Artery Remodeling in a Murine Model of Kawasaki Disease

Stock

Parsons

D'Silva

et al. 2022

Arthritis & Rheumatology

Self Cite

View full text Add to dashboard Cite

Objective Remodeling of the coronary arteries is a common feature in severe cases of Kawasaki disease (KD). This pathology is driven by the dysregulated proliferation of vascular fibroblasts, which can lead to coronary artery aneurysms, stenosis, and myocardial ischemia. We undertook this study to investigate whether inhibiting fibroblast proliferation might be an effective therapeutic strategy to prevent coronary artery remodeling in KD. Method We used a murine model of KD (induced by the injection of the Candida albicans water‐soluble complex [CAWS]) and analyzed patient samples to evaluate potential antifibrotic therapies for KD. Results We identified the mechanistic target of rapamycin (mTOR) pathway as a potential therapeutic target in KD. The mTOR inhibitor rapamycin potently inhibited cardiac fibroblast proliferation in vitro, and vascular fibroblasts up‐regulated mTOR kinase signaling in vivo in the CAWS mouse model of KD. We evaluated the in vivo efficacy of mTOR inhibition and found that the therapeutic administration of rapamycin reduced vascular fibrosis and intimal hyperplasia of the coronary arteries in CAWS‐injected mice. Furthermore, the analysis of cardiac tissue from KD fatalities revealed that vascular fibroblasts localizing with inflamed coronary arteries up‐regulate mTOR signaling, confirming that the mTOR pathway is active in human KD. Conclusion Our findings demonstrate that mTOR signaling contributes to coronary artery remodeling in KD, and that targeting this pathway offers a potential therapeutic strategy to prevent or restrict this pathology in high‐risk KD patients.

show abstract

The Selective Expansion and Targeted Accumulation of Bone Marrow–Derived Macrophages Drive Cardiac Vasculitis

Abstract: The sequences presented in this article have been submitted to the Gene Expression Omnibus (https://www.ncbi.nlm.nih.gov/geo) under accession number GSE120012.

Cited by 11 publications

References 56 publications

Single‐cell RNA sequencing reveals the induction of novel myeloid and myeloid‐associated cell populations in visceral fat with long‐term obesity

Single‐cell RNA sequencing reveals the induction of novel myeloid and myeloid‐associated cell populations in visceral fat with long‐term obesity

The innate and adaptive immune landscape of SARS-CoV-2-associated Multisystem Inflammatory Syndrome in Children (MIS-C) from acute disease to recovery

Mechanistic Target of Rapamycin Inhibition Prevents Coronary Artery Remodeling in a Murine Model of Kawasaki Disease

Contact Info

Product

Resources

About