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The microRNA miR-22 inhibits the histone deacetylase HDAC4 to promote TH17 cell–dependent emphysema

Nature Immunology volume 16, pages 1185–1194 (2015)Cite this article

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Abstract

Smoking-related emphysema is a chronic inflammatory disease driven by the TH17 subset of helper T cells through molecular mechanisms that remain obscure. Here we explored the role of the microRNA miR-22 in emphysema. We found that miR-22 was upregulated in lung myeloid dendritic cells (mDCs) of smokers with emphysema and antigen-presenting cells (APCs) of mice exposed to smoke or nanoparticulate carbon black (nCB) through a mechanism that involved the transcription factor NF-κB. Mice deficient in miR-22, but not wild-type mice, showed attenuated TH17 responses and failed to develop emphysema after exposure to smoke or nCB. We further found that miR-22 controlled the activation of APCs and TH17 responses through the activation of AP-1 transcription factor complexes and the histone deacetylase HDAC4. Thus, miR-22 is a critical regulator of both emphysema and TH17 responses.

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Figure 1: Enhanced miR-22 expression in human emphysema and cigarette smoke–activated lung APCs.
Figure 2: miR-22 deficiency protects mice from nCB-induced emphysema.
Figure 3: miR-22 expression is transcriptionally regulated through NF-κB and AP-1 complexes.
Figure 4: miR-22 promotes the activation of lung APCs.
Figure 5: miR-22 promotes the transcriptional activity of AP-1 in APCs.
Figure 6: miR-22 targets HDAC4 in APCs to promote IL-6 production.
Figure 7: HDAC4 inhibits the activation of APCs and the progression of emphysema.
Figure 8: Neutralization of lung miR-22 reverses nCB-induced emphysema.

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Acknowledgements

We thank J. Levitt (Baylor College of Medicine) for CD11c-Cre mice; E. Olson (UT Southwestern Medical Center) for Hdac4fl mice; and W. Decker, J. Sederstrom, Y. Qian and L.-Z. Song for technical assistance. Supported by the US National Institutes of Health (R01HL117181 to F.K.; R01HL110883 to F.K. and D.B.C.; and AI036211, CA125123 and RR024574 to the Cytometry and Cell Sorting Core at Baylor College of Medicine) and the US Veterans Administration Office of Research and Development (1I01BX002221 to D.B.C.).

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  1. Antony Rodriguez

    Present address: Present address: Department of Physical Therapy, University of Texas Medical Branch Galveston, Galveston, Texas, USA.,

Authors and Affiliations

  1. Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas, USA

    Wen Lu, Ran You, Xiaoyi Yuan, Farrah Kheradmand & David B Corry

  2. Translational Biology and Molecular Medicine Program, Baylor College of Medicine, Houston, Texas, USA

    Tianshu Yang, Farrah Kheradmand & David B Corry

  3. Department of Chemistry, Rice University, Houston, Texas, USA

    Errol L G Samuel, Daniela C Marcano, William K A Sikkema & James M Tour

  4. Department of Human and Molecular Genetics, Baylor College of Medicine, Houston, Texas, USA

    Antony Rodriguez

  5. Department of Medicine, Baylor College of Medicine, Houston, Texas, USA

    Farrah Kheradmand & David B Corry

  6. Biology of Inflammation Center and the Michael E. DeBakey Virginia Center for Translational Research on Inflammatory Diseases, Houston, Texas, USA

    Farrah Kheradmand & David B Corry

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Contributions

W.L. and D.B.C. conceptualized the project and all studies and wrote the manuscript with assistance from all co-authors; W.L. designed and performed all experiments, with R.Y., X.Y. and T.Y. contributing to selected mouse experiments and micro-CT analysis; E.L.G.S., D.C.M., W.K.A.S. and J.M.T. prepared nCB; A.R. provided miR-22 deficient mice; and F.K. and D.B.C. provided grant support.

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Correspondence to Farrah Kheradmand or David B Corry.

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Integrated supplementary information

Supplementary Figure 1 miR-22 is required for airway MMP activities but not for the development of γδ+ T cells in emphysema.

(a) Gelatin zymogram depicting matrix metalloproteinase (MMP) 2 and MMP9 activities in bronchoalveolar lavage fluid (BALF) of wild type (WT; lanes 3-5) and Mir22–/– mice (lanes 6-9) previously challenged with nCB. Lanes 1 and 2 are BALF from naïve wild type mice. (b) Total lung IL-17A+ γδ+ T cells were quantified by flow cytometry.

Supplementary Figure 2 Mir22–/– mice develop reduced TH17 responses upon sensitization with ovalbumin.

Both WT and Mir22–/– mice were intraperitoneally injected with 25µg ovalbumin precipitated in alum weekly for three consecutive weeks. Total splenocytes were harvested at the end of the fifth week. (a) IFN-γ, (b) IL-4 and (c) IL-17A positive cells with ovalbumin (OVA; 0.5 mg/ml overnight) and without (Media) were quantified by ELISpot. *: p<0.05, Kruskal Wallis test. n=4.

Supplementary Figure 3 nCB-induced production of pro-inflammatory cytokines and chemokines from whole lung is in part miR-22 dependent.

WT and Mir22–/– mice were challenged intranasally with nCB over one month. (a-d) Lungs were then collected and the concentrations of the indicated cytokines and chemokines from lung homogenate fluids were determined by Bio-plex. (e-g) Lung CD11c+ cells were isolated and cultured ex vivo overnight. Concentrations of the indicated supernatant chemokines were determined by Bio-plex. *: p<0.05; **: p<0.01, ***: p<0.001, Kruskal Wallis test. n=4-5.

Supplementary Figure 4 Smoke-exposed wild-type lung APCs are sufficient to induce emphysema in mice with and without miR-22.

Lung CD11c+ APC from four month cigarette SMK or air exposed WT mice were isolated and adaptively transferred to WT and Mir22–/– recipients. (a) Micro-CT quantification of recipient mouse lung volume after 3 months. (b) Total macrophages in BALF. (c) Relative abundance of lung IL-17A+ TH17 cells as assessed by flow cytometry. *: p<0.05; **: p<0.01, Kruskal Wallis test. n=3-4 as indicated in (A).

Supplementary Figure 5 PPAR-γ regulates miR-22 expression in lung APCs.

(a) MiR-22 expression in CD11c+ lung APCs from eight month old Ppargflox and PpargCD11c mice. (b) MiR-22 expression in CD11c+ lung APCs from air or cigarette smoke (SMK) exposed mice with or without intranasally challenge of ciglitazone (Cig). *: p<0.05; unpaired t-test in (a) one-way ANOVA test in (b). (n=3)

Supplementary Figure 6 miR-22 is required for pro-inflammatory gene expression in nCB-exposed lung APCs.

Lung CD11c+ cells from WT and Mir22–/– mice exposed to PBS or nCB were isolated. Expression of indicated genes was determined by quantitative PCR. *, p<0.05; **, p<0.01; ***, p<0.001, One-way ANOVA test. (n=3)

Supplementary Figure 7 miR-22 deficient APCs induce a TH17 cytokine in vitro with supplementation of IL-6.

MiR-22 sufficient (Mir22flox) and deficient BMDCs (Mir22CD11c) were primed with or without 1000ng nCB and co-cultured with WT naïve CD4+ T cells for 3 days and secreted IL-17A was measured by ELISA (n=4-5). 10ng/ml IL-6 supplement was added as indicated. *: p<0.05; Mann-Whitney test (n=4-5).

Supplementary Figure 8 Silencing miR-22 alters pro- and anti-inflammatory gene expression in APCs.

Mice were sacrificed at the 5 month point in Figure (8a). (a) MiR-22 expression level in lung CD11c+ cells. IL-6 (b) and IL-17A (c) concentration in lung homogenates as assessed by Bioplex. (d-f) Indicated gene expression in isolated lung CD11c+ cells determined by RT-qPCR. *, p<0.05; **, p<0.01; ***, p<0.001, Kruskal Wallis test (n=4-6). Data in are from one of two comparable experiments.

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Lu, W., You, R., Yuan, X. et al. The microRNA miR-22 inhibits the histone deacetylase HDAC4 to promote TH17 cell–dependent emphysema. Nat Immunol 16, 1185–1194 (2015). https://doi.org/10.1038/ni.3292

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