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Sci Immunol. 2019 Oct 11;4(40). pii: eaax4783. doi: 10.1126/sciimmunol.aax4783.

Interleukin-36γ-producing macrophages drive IL-17-mediated fibrosis.

Author information

1
Translational Tissue Engineering Center, Wilmer Eye Institute, and Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
2
Institute for Cell Engineering, Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
3
Bloomberg~Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
4
Division of Dermatopathology, Johns Hopkins Hospital, Baltimore, MD, USA.
5
Translational Tissue Engineering Center, Wilmer Eye Institute, and Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA. jhe@jhu.edu.

Abstract

Biomaterials induce an immune response and mobilization of macrophages, yet identification and phenotypic characterization of functional macrophage subsets in vivo remain limited. We performed single-cell RNA sequencing analysis on macrophages sorted from either a biologic matrix [urinary bladder matrix (UBM)] or synthetic biomaterial [polycaprolactone (PCL)]. Implantation of UBM promotes tissue repair through generation of a tissue environment characterized by a T helper 2 (TH2)/interleukin (IL)-4 immune profile, whereas PCL induces a standard foreign body response characterized by TH17/IL-17 and fibrosis. Unbiased clustering and pseudotime analysis revealed distinct macrophage subsets responsible for antigen presentation, chemoattraction, and phagocytosis, as well as a small population with expression profiles of both dendritic cells and skeletal muscle after UBM implantation. In the PCL tissue environment, we identified a CD9hi+IL-36γ+ macrophage subset that expressed TH17-associated molecules. These macrophages were virtually absent in mice lacking the IL-17 receptor, suggesting that they might be involved in IL-17-dependent immune and autoimmune responses. Identification and comparison of the unique phenotypical and functional macrophage subsets in mouse and human tissue samples suggest broad relevance of the new classification. These distinct macrophage subsets demonstrate previously unrecognized myeloid phenotypes involved in different tissue responses and provide targets for potential therapeutic modulation in tissue repair and pathology.

PMID:
31604843
DOI:
10.1126/sciimmunol.aax4783

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