MicroRNA-223 controls susceptibility to tuberculosis by regulating lung neutrophil recruitment
Anca Dorhoi, Marco Iannaccone, Maura Farinacci, Kellen C. Faé, Jörg Schreiber, Pedro Moura-Alves, Geraldine Nouailles, Hans-Joachim Mollenkopf, Dagmar Oberbeck-Müller, Sabine Jörg, Ellen Heinemann, Karin Hahnke, Delia Löwe, Franca Del Nonno, Delia Goletti, Rosanna Capparelli, Stefan H.E. Kaufmann
Anca Dorhoi, Marco Iannaccone, Maura Farinacci, Kellen C. Faé, Jörg Schreiber, Pedro Moura-Alves, Geraldine Nouailles, Hans-Joachim Mollenkopf, Dagmar Oberbeck-Müller, Sabine Jörg, Ellen Heinemann, Karin Hahnke, Delia Löwe, Franca Del Nonno, Delia Goletti, Rosanna Capparelli, Stefan H.E. Kaufmann
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Research Article Pulmonology

MicroRNA-223 controls susceptibility to tuberculosis by regulating lung neutrophil recruitment

Abstract

The molecular mechanisms that control innate immune cell trafficking during chronic infection and inflammation, such as in tuberculosis (TB), are incompletely understood. During active TB, myeloid cells infiltrate the lung and sustain local inflammation. While the chemoattractants that orchestrate these processes are increasingly recognized, the posttranscriptional events that dictate their availability are unclear. We identified microRNA-223 (miR-223) as an upregulated small noncoding RNA in blood and lung parenchyma of TB patients and during murine TB. Deletion of miR-223 rendered TB-resistant mice highly susceptible to acute lung infection. The lethality of miR-223–/– mice was apparently not due to defects in antimycobacterial T cell responses. Exacerbated TB in miR-223–/– animals could be partially reversed by neutralization of CXCL2, CCL3, and IL-6, by mAb depletion of neutrophils, and by genetic deletion of Cxcr2. We found that miR-223 controlled lung recruitment of myeloid cells, and consequently, neutrophil-driven lethal inflammation. We conclude that miR-223 directly targets the chemoattractants CXCL2, CCL3, and IL-6 in myeloid cells. Our study not only reveals an essential role for a single miRNA in TB, it also identifies new targets for, and assigns biological functions to, miR-223. By regulating leukocyte chemotaxis via chemoattractants, miR-223 is critical for the control of TB and potentially other chronic inflammatory diseases.

Authors

Anca Dorhoi, Marco Iannaccone, Maura Farinacci, Kellen C. Faé, Jörg Schreiber, Pedro Moura-Alves, Geraldine Nouailles, Hans-Joachim Mollenkopf, Dagmar Oberbeck-Müller, Sabine Jörg, Ellen Heinemann, Karin Hahnke, Delia Löwe, Franca Del Nonno, Delia Goletti, Rosanna Capparelli, Stefan H.E. Kaufmann

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Figure 5

Lung influx of innate cells during TB is modulated by miR-223.

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Lung influx of innate cells during TB is modulated by miR-223. (A) Rel...
(A) Relative gene expression of selected genes in lung tissue of miR-223–/– compared with C57BL/6 (WT) mice on days 0 and 21 p.i., as identified by microarray gene chip assay. Data are presented as the mean ± SEM and are combined from two independent experiments (n = 9–11). (B) qRT-PCR of genes differentially expressed in respiratory parenchyma of miR-223–/– animals. Gapd was used as a reference gene, and data were normalized to uninfected mice. Data are presented as the mean ± SEM and are pooled from two independent experiments; Student’s t test (n = 9–11). (C) Concentrations of CXCL2, CCL3, and IL-6 were measured using a multiplex immunoassay in lung homogenates collected 21 days p.i. Data are presented as the mean ± SEM and are pooled from four independent experiments; ANOVA with Bonferroni’s post test (n = 18–24). (D) Giemsa staining and immunohistochemistry for neutrophils (PMNs) and inflammatory monocytes/macrophages (MPO) in lung tissue collected on days 25 and 21 p.i. Data are representative of two independent experiments (n = 5). Scale bars: 100 μm. (E) Frequency and number of alveolar macrophages (AM), inflammatory macrophages (iM), and neutrophils (PMN) isolated from the lungs of miR233–/– and WT infected animals on days 7, 14, and 21 p.i. Data are presented as the mean ± SEM and are pooled from two independent experiments; ANOVA with Bonferroni’s post test (n = 9–10). *P < 0.05; **P < 0.01; ***P < 0.001.