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Cited by 70Interstitial Lung Diseases and Idiopathic Pulmonary FibrosisMicroRNA in disease regulationPulmonary Hypertension Research and Treatments

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

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Ahangari, Farida, Price, Nathan L., Malik, Shipra, Chioccioli, Maurizio, Bärnthaler, Thomas, Adams, Taylor S., Kim, Jooyoung, Pradeep, Sai Pallavi +19 more·2023·JCI Insight
DOI 10.1172/jci.insight.158100PMC PMC9977502
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Abstract

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 sterol regulatory element binding protein ( SREBP ) genes are master regulators of sterol and fatty acid (FA) metabolism. miR-33 controls macrophage immunometabolic response and enhances mitochondrial biogenesis, FA oxidation, and cholesterol efflux. Here, we show that miR-33 levels are increased in bronchoalveolar lavage (BAL) cells isolated from patients with IPF compared with 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. These studies elucidate a major role of miR-33 in macrophages in the regulation of pulmonary fibrosis and uncover a potentially novel therapeutic approach to treat this disease.

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  • Inhibition of miR-33a or miR-33a deletion in macrophages affects myeloid cell differentiation, induces M2 macrophage polarization with mitochondrial respiratory and metabolic changes, and enhances autophagy.

    “Inhibition of miR-33a or miR-33a deletion in macrophages has been shown to affect myeloid cell differentiation 25) , induce M2 macrophage polarization with mitochondrial respiratory and metabolic changes 26 , 27) , and enhance autophagy 28 , 29) .”

    From Critical Role of microRNA-33a/b in Cardiovascular and Metabolic Disease: Molecular Mechanisms and Therapeutic Perspectives (2026) · cites this paper as [29]

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Authors
Ahangari, F., Price, N. L., Malik, S., Chioccioli, M., Bärnthaler, T., Adams, T. S., Kim, J., Pradeep, S. P., Ding, S., Cosmos, C., Rose, K.-A. S., McDonough, J. E., Aurelien, N. R., Ibarra, G., Omote, N., Schupp, J. C., DeIuliis, G., Villalba Nunez, J. A., Sharma, L., Ryu, C., Dela Cruz, C. S., Liu, X., Prasse, A., Rosas, I., Bahal, R., Fernández-Hernando, C., & Kaminski, N.
Affiliations
  • Yale University (US)
  • National Institutes of Health (US)
  • University of Connecticut (US)
  • Medical University of Graz (AT)
  • Rhode Island Hospital (US)
  • Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA.
  • Section of Pulmonary, Critical Care and Sleep Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.
  • Leibniz University Hannover (DE)
  • Vascular Biology and Therapeutics Program, Yale Center for Molecular and System Metabolism, Department of Comparative Medicine, and Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA.
Corresponding author
Kaminski, Naftali
ORCID
Venue
JCI Insight
Publisher
American Society for Clinical Investigation
Published
2023-02-22
Volume
8
Issue
4
ISSN
2379-3708 (ISSN-L)
DOI
10.1172/jci.insight.158100
PMC
PMC9977502
OpenAlex
W4315436731
Cited by
70
References
13
Citations by year
2026: 17 · 2025: 23 · 2024: 17 · 2023: 13
FWCI
12.84
Type
journal article
Language
en
Open access
Licence
Locations
  • JCI Insight (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Fraunhofer-Publica (Fraunhofer-Gesellschaft) (submittedVersion)
Funders
National Heart, Lung, and Blood Institute (R35HL135820, R01HL141852, R01HL127349, U01HL145567, U01HL122626)
Topics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Pulmonary Hypertension Research and Treatments
Keywords
microRNA-33, macrophages, idiopathic pulmonary fibrosis, pulmonary fibrosis, autophagy, mitochondrial homeostasis, SREBP, fatty acid metabolism, immunometabolism, bleomycin-induced fibrosis, inflammation
MeSH terms
Animals, Autophagy, Bleomycin, Homeostasis, Humans, Macrophages, Mitochondria, MicroRNAs, Mice, Idiopathic Pulmonary Fibrosis

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