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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