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.
| Original language | English |
|---|---|
| Pages (from-to) | 4836-4848 |
| Number of pages | 13 |
| Journal | Journal of Clinical Investigation |
| Volume | 123 |
| Issue number | 11 |
| DOIs | |
| Publication status | Published - Nov 1 2013 |
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ASJC Scopus subject areas
- Medicine(all)
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MicroRNA-223 controls susceptibility to tuberculosis by regulating lung neutrophil recruitment. / Dorhoi, Anca; Iannaccone, Marco; Farinacci, Maura; Faé, Kellen C.; Schreiber, Jörg; Moura-Alves, Pedro; Nouailles, Geraldine; Mollenkopf, Hans Joachim; Oberbeck-Müller, Dagmar; Jörg, Sabine; Heinemann, Ellen; Hahnke, Karin; Löwe, Delia; Del Nonno, Franca; Goletti, Delia; Capparelli, Rosanna; Kaufmann, Stefan H E.
In: Journal of Clinical Investigation, Vol. 123, No. 11, 01.11.2013, p. 4836-4848.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - MicroRNA-223 controls susceptibility to tuberculosis by regulating lung neutrophil recruitment
AU - Dorhoi, Anca
AU - Iannaccone, Marco
AU - Farinacci, Maura
AU - Faé, Kellen C.
AU - Schreiber, Jörg
AU - Moura-Alves, Pedro
AU - Nouailles, Geraldine
AU - Mollenkopf, Hans Joachim
AU - Oberbeck-Müller, Dagmar
AU - Jörg, Sabine
AU - Heinemann, Ellen
AU - Hahnke, Karin
AU - Löwe, Delia
AU - Del Nonno, Franca
AU - Goletti, Delia
AU - Capparelli, Rosanna
AU - Kaufmann, Stefan H E
PY - 2013/11/1
Y1 - 2013/11/1
N2 - 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.
AB - 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.
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U2 - 10.1172/JCI67604
DO - 10.1172/JCI67604
M3 - Article
AN - SCOPUS:84887488025
VL - 123
SP - 4836
EP - 4848
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
SN - 0021-9738
IS - 11
ER -