IL-16/miR-125a axis controls neutrophil recruitment in pristane-induced lung inflammation
Siobhan Smith, Pei Wen Wu, Jane J. Seo, Thilini Fernando, Mengyao Jin, Jorge Contreras, Erica N. Montano, Joan Ní Gabhann, Kyle Cunningham, Amro Widaa, Eoghan M. McCarthy, Eamonn S. Molloy, Grainne Kearns, Conor C. Murphy, Weiping Kong, Harry Björkbacka, Hardy Kornfeld, Lindsy Forbess, Swamy Venuturupalli, Mariko Ishimori, Daniel Wallace, Michael H. Weisman, Caroline A. Jefferies
Siobhan Smith, Pei Wen Wu, Jane J. Seo, Thilini Fernando, Mengyao Jin, Jorge Contreras, Erica N. Montano, Joan Ní Gabhann, Kyle Cunningham, Amro Widaa, Eoghan M. McCarthy, Eamonn S. Molloy, Grainne Kearns, Conor C. Murphy, Weiping Kong, Harry Björkbacka, Hardy Kornfeld, Lindsy Forbess, Swamy Venuturupalli, Mariko Ishimori, Daniel Wallace, Michael H. Weisman, Caroline A. Jefferies
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Research Article Immunology

IL-16/miR-125a axis controls neutrophil recruitment in pristane-induced lung inflammation

Abstract

Severe lung inflammation and alveolar hemorrhage can be life-threatening in systemic lupus erythematosus (SLE) patients if not treated early and aggressively. Neutrophil influx is the driver key of this pathology, but little is known regarding the molecular events regulating this recruitment. Here, we uncover a role for IL-16/mir-125a in this pathology and show not only that IL-16 is a target for miR-125a but that reduced miR-125a expression in SLE patients associates with lung involvement. Furthermore, in the pristane model of acute “SLE-like” lung inflammation and alveolar hemorrhage, we observed reduced pulmonary miR-125a and enhanced IL-16 expression. Neutrophil infiltration was markedly reduced in the peritoneal lavage of pristane-treated IL-16–deficient mice and elevated following i.n. delivery of IL-16. Moreover, a miR-125a mimic reduced pristane-induced IL-16 expression and neutrophil recruitment and rescued lung pathology. Mechanistically, IL-16 acts directly on the pulmonary epithelium and markedly enhances neutrophil chemoattractant expression both in vitro and in vivo, while the miR-125a mimic can prevent this. Our results reveal a role for miR-125a/IL-16 in regulating lung inflammation and suggest this axis may be a therapeutic target for management of acute lung injury in SLE.

Authors

Siobhan Smith, Pei Wen Wu, Jane J. Seo, Thilini Fernando, Mengyao Jin, Jorge Contreras, Erica N. Montano, Joan Ní Gabhann, Kyle Cunningham, Amro Widaa, Eoghan M. McCarthy, Eamonn S. Molloy, Grainne Kearns, Conor C. Murphy, Weiping Kong, Harry Björkbacka, Hardy Kornfeld, Lindsy Forbess, Swamy Venuturupalli, Mariko Ishimori, Daniel Wallace, Michael H. Weisman, Caroline A. Jefferies

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Figure 3

In vivo delivery of miR-125a mimic reduces neutrophil recruitment and IL-16 expression and attenuates pristane-induced lung pathology.

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In vivo delivery of miR-125a mimic reduces neutrophil recruitment and IL...
(A–F) Mice received a single i.p. injection (10 nmol) of a miR-125a mimic or negative control (n = 10 for each treatment group) for 1 day before the i.p. injection of 500 ml pristane followed by sacrifice at 10 days for analysis. (A) Expression of miR-125a is altered in the lungs following administration of miR-125a compared with negative control. (B) Il-16 levels in the different treatment groups were analyzed in the lungs by qPCR. (C and D) Flow cytometry of cell populations in lung digests of the different treatment groups was performed. Percentage of IL-16–expressing cells (C) and neutrophils (D) in the lung. (E and F) Percentage of IL-16–expressing (E) Ly6G+ neutrophils and (F) CD4+ T cells following intracellular detection of IL-16 by flow cytometry. (G and H) Expression of (G) Isg15 and (H) Mx1 in the lungs of the different treatment groups analyzed by qPCR. For A, B, E, and F, data shown represent mean ± SD. *P ≤ 0.05, **P ≤ 0.01 as determined by unpaired t test. For C, D, G, and H, data shown represent mean ± SEM. *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001 as determined by 1-way ANOVA.