Targeting Myeloid Dependent MicroRNAs in Acute Respiratory Distress Syndrome

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Abstract Lung inflammation is one of the profound contributors to acute respiratory distress syndrome (ARDS). The initial acute lung inflammation in response to infection or tissue injury leads to profound infiltration of leukocytes and the release of inflammatory cytokines. Myeloid cells, including macrophages, are key players mediating the onset and resolution of acute lung inflammation. However, the triggers that reprogram macrophages to control excessive inflammation remain incompletely understood. Recent work has demonstrated a key role for microRNAs (miRNAs) in inflammatory diseases. However, little research has been done to assess the functional role of miRNAs in macrophages in the context of controlling lung inflammation. We hypothesize that control of lung inflammation involves the transcriptional induction of specific miRNAs in macrophages. Our study has identified microRNA-147 (miR-147) to be dramatically increased in recruited macrophages during lung inflammation. The induction of miR-147 is dependent on hypoxia-inducible factor 1A. Functionally, miR- 147 controls macrophage inflammation in vitro, and myeloid-derived miR-147 dampens lung inflammation in vivo. We identified and confirmed the mitochondria complex associated protein NDUFA4 as a leading miR-147 target. New and exciting preliminary data indicated that by targeting NDUFA4, miR-147 dampens the production of inflammatory cytokines such as IL-6, IL-1β, and TNFα in macrophages. Additional evidence supports that inhibition of succinate oxidation and concomitant histone hypermethylation contributes to the miR-147/NDUFA4 mediated effect. Finally, overexpression of miR-147 improves the recovery from lung inflammation in vivo. Here, we test the hypothesis that the miR- 147/NDUFA4 axis represents an endogenous protective pathway in macrophages to control lung inflammation. The following three aims have been proposed to test this hypothesis. In Aim 1, we will use state-of-art miR- 147 reporter mice to study the transcriptional regulation of miR-147 and investigate how miR- 147/NDUFA4 axis controls macrophage inflammation in vitro. In Aim 2, we will perform proof-of-principle studies in human ARDS and employ cutting-edge transgenic mice to investigate the functional role of miR-147/NDUFA4 axis in macrophages during lung inflammation in vivo. In Aim 3, we will further explore the therapeutic targeting of miR-147/NDUFA4 axis in modulating lung inflammation. The completion of the proposed study will identify miRNA targets as an innovative therapeutic approach for ARDS.