Advertisement

microRNA-33 deficiency in macrophages enhances autophagy, improves mitochondrial homeostasis, and protects against lung fibrosis

Farida Ahangari,¹ Nathan L. Price,² Shipra Malik,³ Maurizio Chioccioli,¹ Thomas Bärnthaler,¹ Taylor S. Adams,¹ Jooyoung Kim,¹ Sai Pallavi Pradeep,³ Shuizi Ding,¹ Carlos Cosme Jr,¹ Kadi-Ann S. Rose,¹ John E. McDonough,⁴ Nachelle R. Aurelien,¹ Gabriel Ibarra,¹ Norihito Omote,¹ Jonas C. Schupp,¹ Giuseppe DeIuliis,¹ Julian A. Villalba Nunez,⁵ Lokesh Sharma,¹ Changwan Ryu,¹ Charles S. Dela Cruz,¹ Xinran Liu,⁶ Antje Prasse,⁷ Ivan Rosas,⁸ Raman Bahal,³ Carlos Fernandez-Hernando,² and Naftali Kaminski¹

Published January 10, 2023 - More info

Idiopathic pulmonary fibrosis (IPF) is a progressive and ultimately fatal disease. Recent findings have shown a marked metabolic reprogramming associated with changes in mitochondrial homeostasis and autophagy during pulmonary fibrosis. The microRNA-33 (miR-33) family of microRNAs (miRNAs) encoded within the introns of SREBP (sterol regulatory element binding protein) genes are master regulators of sterol and fatty acid (FA) metabolism. miR-33 controls macrophage immuno-metabolic response and enhances mitochondrial biogenesis, FA oxidation, and cholesterol efflux. Here, we show that miR-33 levels are increased in Broncho Alveolar Lavage (BAL) cells isolated from IPF patients compared to healthy controls. We demonstrate that specific genetic ablation of miR-33 in macrophages protects against bleomycin-induced pulmonary fibrosis. The absence of miR-33 in macrophages improves mitochondrial homeostasis and increases autophagy while decreasing inflammatory response after bleomycin injury. Notably, pharmacological inhibition of miR-33 in macrophages via administration of anti-miR-33 Peptide Nucleic Acids (PNA-33) attenuates fibrosis in different in vivo and ex vivo mice and human models of pulmonary fibrosis. Together, these studies elucidate a major role of miR-33 in macrophages in the regulation of pulmonary fibrosis and uncover a novel therapeutic approach to treat this disease.

Advertisement

Advertisement