A long noncoding RNA regulates inflammation resolution by mouse macrophages through fatty acid oxidation activation.

Abstract

Proper resolution of inflammation is vital for repair and restoration of homeostasis after tissue damage, and its dysregulation underlies various noncommunicable diseases, such as cardiovascular and metabolic diseases. Macrophages play diverse roles throughout initial inflammation, its resolution, and tissue repair. Differential metabolic reprogramming is reportedly required for induction and support of the various macrophage activation states. Here we show that a long noncoding RNA (lncRNA), <i>lncFAO</i>, contributes to inflammation resolution and tissue repair in mice by promoting fatty acid oxidation (FAO) in macrophages. <i>lncFAO</i> is induced late after lipopolysaccharide (LPS) stimulation of cultured macrophages and in Ly6C^hi monocyte-derived macrophages in damaged tissue during the resolution and reparative phases. We found that <i>lncFAO</i> directly interacts with the HADHB subunit of mitochondrial trifunctional protein and activates FAO. <i>lncFAO</i> deletion impairs resolution of inflammation related to endotoxic shock and delays resolution of inflammation and tissue repair in a skin wound. These results demonstrate that by tuning mitochondrial metabolism, <i>lncFAO</i> acts as a node of immunometabolic control in macrophages during the resolution and repair phases of inflammation.