Background Severe lung inflammation and alveolar hemorrhage can be life threatening in lupus patients. Neutrophil influx is the key driver of this pathology. MiR-125a expression is decreased in patients with lupus pneumonitis. IL-16 is a novel target for mir-125a.
Methods Sera and monocytes from 42 SLE patients, 16 with pulmonary involvement was obtained. Gene expression profiles of monocytes from healthy controls and SLE patients were analyzed by qPCR and correlated with disease activity and organ involvement. Monocytes were transfected with mir-125a mimics and antagomirs and effects on IL-16 mRNA determined by qPCR. Biotin-labelled mir-125a mimics were immunoprecipitated from monocytes and IL-16 confirmed as a direct target by qPCR. Autoimmune lung inflammation was measured following intraperitoneal injection of pristane followed by FACs and qPCR analysis of cell populations in the lung.
Results Reduced miR-125a and enhanced IL-16 expression in SLE patient monocytes was observed and found to correlate with lung involvement. Furthermore, in the pristane model of acute ‘SLE-like’ lung inflammation, and alveolar hemorrhage, we observe reduced pulmonary miR-125a and enhanced IL-16 expression. Neutrophil infiltration was markedly reduced in the peritoneal lavage of pristine-treated IL-16 deficient mice and elevated following intranasal delivery of IL-16. Moreover, a miR-125a mimic reduces pristane-induced IL-16 expression and neutrophil recruitment, and rescues lung pathology. Mechanistically, IL-16 acts directly on the pulmonary epithelium and markedly enhances neutrophil chemoattractant expression both in vitro and in vivo, whilst the miR-125a mimic can prevent this.
Conclusions A miR-125a mimic reduces pristane-induced IL-16 expression and neutrophil recruitment, and rescues 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. A novel role for miR-125a/IL-16 in regulating lung inflammation suggests that this axis may be a therapeutic target for management of acute lung injury in SLE.
Acknowledgement Support provided by NIH Grant (HL0127384), Lupus Research Allliance (ALR/TIL332436), Irish Research Council (GO1PD/2014/512).
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