B7H3-dependent myeloid-derived suppressor cell recruitment and activation in pulmonary fibrosis
Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease without effective curative therapy. Recent evidence shows increased circulating myeloid-derived suppressor cells (MDSCs) in cancer, inflammation, and fibrosis, with some of these cells expressing B7H3. We sought to investigat...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-08-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2022.901349/full |
| _version_ | 1811321357210746880 |
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| author | Tianju Liu Francina Gonzalez De Los Santos Andrew E. Rinke Chuling Fang Kevin R. Flaherty Sem H. Phan |
| author_facet | Tianju Liu Francina Gonzalez De Los Santos Andrew E. Rinke Chuling Fang Kevin R. Flaherty Sem H. Phan |
| author_sort | Tianju Liu |
| collection | DOAJ |
| description | Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease without effective curative therapy. Recent evidence shows increased circulating myeloid-derived suppressor cells (MDSCs) in cancer, inflammation, and fibrosis, with some of these cells expressing B7H3. We sought to investigate the role of MDSCs in IPF and its potential mediation via B7H3. Here we prospectively collected peripheral blood samples from IPF patients to analyze for circulating MDSCs and B7H3 expression to assess their clinical significance and potential impact on co-cultured lung fibroblasts and T-cell activation. In parallel, we assess MDSC recruitment and potential B7H3 dependence in a mouse model of pulmonary fibrosis. Expansion of MDSCs in IPF patients correlated with disease severity. Co-culture of soluble B7H3 (sB7H3)-treated mouse monocytic MDSCs (M-MDSCs), but not granulocytic MDSCs (G-MDSCs), activated lung fibroblasts and myofibroblast differentiation. Additionally, sB7H3 significantly enhanced MDSC suppression of T-cell proliferation. Activated M-MDSCs displayed elevated TGFβ and Arg1 expression relative to that in G-MDSCs. Treatment with anti-B7H3 antibodies inhibited bone marrow-derived MDSC recruitment into the bleomycin-injured lung, accompanied by reduced expression of inflammation and fibrosis markers. Selective telomerase reverse transcriptase (TERT) deficiency in myeloid cells also diminished MDSC recruitment associated with the reduced plasma level of sB7H3, lung recruitment of c-Kit+ hematopoietic progenitors, myofibroblast differentiation, and fibrosis. Lung single-cell RNA sequencing (scRNA-seq) revealed fibroblasts as a predominant potential source of sB7H3, and indeed the conditioned medium from activated mouse lung fibroblasts had a chemotactic effect on bone marrow (BM)-MDSC, which was abolished by B7H3 blocking antibody. Thus, in addition to their immunosuppressive activity, TERT and B7H3-dependent MDSC expansion/recruitment from BM could play a paracrine role to activate myofibroblast differentiation during pulmonary fibrosis with potential significance for disease progression mediated by sB7H3. |
| first_indexed | 2024-04-13T13:15:14Z |
| format | Article |
| id | doaj.art-7807b9c2dd51455286770612e2e888b5 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-13T13:15:14Z |
| publishDate | 2022-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-7807b9c2dd51455286770612e2e888b52022-12-22T02:45:29ZengFrontiers Media S.A.Frontiers in Immunology1664-32242022-08-011310.3389/fimmu.2022.901349901349B7H3-dependent myeloid-derived suppressor cell recruitment and activation in pulmonary fibrosisTianju Liu0Francina Gonzalez De Los Santos1Andrew E. Rinke2Chuling Fang3Kevin R. Flaherty4Sem H. Phan5Departments of Pathology, University of Michigan Medical School, Ann Arbor, MI, United StatesDepartments of Pathology, University of Michigan Medical School, Ann Arbor, MI, United StatesDepartments of Pathology, University of Michigan Medical School, Ann Arbor, MI, United StatesDepartments of Pathology, University of Michigan Medical School, Ann Arbor, MI, United StatesDivision of Pulmonary/Critical Care Medicine, University of Michigan Medical School, Ann Arbor, MI, United StatesDepartments of Pathology, University of Michigan Medical School, Ann Arbor, MI, United StatesIdiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease without effective curative therapy. Recent evidence shows increased circulating myeloid-derived suppressor cells (MDSCs) in cancer, inflammation, and fibrosis, with some of these cells expressing B7H3. We sought to investigate the role of MDSCs in IPF and its potential mediation via B7H3. Here we prospectively collected peripheral blood samples from IPF patients to analyze for circulating MDSCs and B7H3 expression to assess their clinical significance and potential impact on co-cultured lung fibroblasts and T-cell activation. In parallel, we assess MDSC recruitment and potential B7H3 dependence in a mouse model of pulmonary fibrosis. Expansion of MDSCs in IPF patients correlated with disease severity. Co-culture of soluble B7H3 (sB7H3)-treated mouse monocytic MDSCs (M-MDSCs), but not granulocytic MDSCs (G-MDSCs), activated lung fibroblasts and myofibroblast differentiation. Additionally, sB7H3 significantly enhanced MDSC suppression of T-cell proliferation. Activated M-MDSCs displayed elevated TGFβ and Arg1 expression relative to that in G-MDSCs. Treatment with anti-B7H3 antibodies inhibited bone marrow-derived MDSC recruitment into the bleomycin-injured lung, accompanied by reduced expression of inflammation and fibrosis markers. Selective telomerase reverse transcriptase (TERT) deficiency in myeloid cells also diminished MDSC recruitment associated with the reduced plasma level of sB7H3, lung recruitment of c-Kit+ hematopoietic progenitors, myofibroblast differentiation, and fibrosis. Lung single-cell RNA sequencing (scRNA-seq) revealed fibroblasts as a predominant potential source of sB7H3, and indeed the conditioned medium from activated mouse lung fibroblasts had a chemotactic effect on bone marrow (BM)-MDSC, which was abolished by B7H3 blocking antibody. Thus, in addition to their immunosuppressive activity, TERT and B7H3-dependent MDSC expansion/recruitment from BM could play a paracrine role to activate myofibroblast differentiation during pulmonary fibrosis with potential significance for disease progression mediated by sB7H3.https://www.frontiersin.org/articles/10.3389/fimmu.2022.901349/fullB7H3TERTlungfibrosismyeloid-derived suppressor cell (MDSC) |
| spellingShingle | Tianju Liu Francina Gonzalez De Los Santos Andrew E. Rinke Chuling Fang Kevin R. Flaherty Sem H. Phan B7H3-dependent myeloid-derived suppressor cell recruitment and activation in pulmonary fibrosis Frontiers in Immunology B7H3 TERT lung fibrosis myeloid-derived suppressor cell (MDSC) |
| title | B7H3-dependent myeloid-derived suppressor cell recruitment and activation in pulmonary fibrosis |
| title_full | B7H3-dependent myeloid-derived suppressor cell recruitment and activation in pulmonary fibrosis |
| title_fullStr | B7H3-dependent myeloid-derived suppressor cell recruitment and activation in pulmonary fibrosis |
| title_full_unstemmed | B7H3-dependent myeloid-derived suppressor cell recruitment and activation in pulmonary fibrosis |
| title_short | B7H3-dependent myeloid-derived suppressor cell recruitment and activation in pulmonary fibrosis |
| title_sort | b7h3 dependent myeloid derived suppressor cell recruitment and activation in pulmonary fibrosis |
| topic | B7H3 TERT lung fibrosis myeloid-derived suppressor cell (MDSC) |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2022.901349/full |
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