Background/Purpose: MiR-155 is a typical pleiotropic miRNA that participates in various aspects of immunity. Previous in vitro studies indicated that it is both a pro-inflammatory and an anti-inflammatory regulator. Furthermore, studies in multiple mouse models (LPS shock, EAE, and CIA) revealed a pathogenic role of this miRNA in the development of tissue damage. Also, miR-155 is abnormally overexpressed among different lupus mouse models. However, aspects of the role of miR-155 in lupus acute tissue damage remain unclear. In this study, we systemically examined the role of miR-155 in the development of pulmonary hemorrhage (PH) in Pristane-induced lupus, by assessing the effect of the administration of chemically modified complementary oligonucleotides of miR-155, called the miR-155 antagomir.

Methods:  Pristane-induced PH mouse model was established as previously reported. Briefly, miR-155 knockout (KO) and wild type (WT) control mice received a single i.p injection of 0.5 ml pristane. After 14 days, lung tissues were collected for pathologic assessment. The dynamic expression of miR-155 was evaluated 1, 3, 7, 14 days post Pristane injection. In intervention experiments, the mice were divided into two groups, receiving respectively three consecutive i.v injections of miR-155 antagomir (miRNA inhibitor) (n=5) or random sequence antagomir negative control (n=5) 3 days before Pristane injection. Two weeks later, the prevalence of PH was evaluated by H&E staining. Total lung RNAs were assayed by qPCR or subjected to gene profiling. Gene profiling data was analyzed by IPA software. Serum cytokines were messured by Bio-plex Pro^TM Assays. 

Results: We showed that miR-155 was elevated in lung tissues in the process of PH induced by Pristane. MiR-155 KO mice appeared to develop attenuated PH, with reduced levels of pro-inflammatory cytokines (TNF-a, IL-6, IL-1β) in sera and target tissues. IPA analysis of gene profiling data indicated that IL-6 signaling pathway was dramatically activated in WT mice but not in miR-155 KO mice 7 day post pristane injection. By integrating the gene expression profiling data from miR-155 KO mice with microRNA target predication, our data suggest that PPARα, an anti-inflammatory transcription factor, is a novel functional target of miR-155. Furthermore, we showed that in vivo silencing of miR-155 by a synthetic miRNA inhibitor­­­­—miR-155 antagomir significantly ameliorated PH induced by Pristane (miR-155 antagomir: 20% PH; random sequence antagomir negative control: 80% PH). Consistently, the pro-inflammatory cytokines (TNF-a, IL-6, IL-1β) were reduced upon miR-155 silencing. 

Conclusion: Overall, our study shows that knockdown of miR-155 by miR-155 antagomir inhibits Pristane induced PH through reducing the production of pro-inflammatory cytokines. This finding suggests a promising therapeutic potential of miR-155 antagonist in the treatment of acute lung inflammation in lupus and reinforces the conclusion that antagomir may prove to be a very effective general therapeutic strategy for human disease.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/in-vivo-therapeutic-success-of-microrna-155-mir-155-antagomir-in-a-mouse-model-of-lupus-pulmonary-hemorrhage/