title: MicroRNA-34a Negatively Regulates Efferocytosis by Tissue Macrophages in Part via SIRT1.
abstract: Apoptotic cell (AC) clearance (efferocytosis) is an evolutionarily conserved process essential for immune health, particularly to maintain self-tolerance. Despite identification of many recognition receptors and intracellular signaling components of efferocytosis, its negative regulation remains incompletely understood and has not previously been known to involve microRNAs (miRs). In this article, we show that miR-34a (gene ID 407040), well recognized as a p53-dependent tumor suppressor, mediates coordinated negative regulation of efferocytosis by resident murine and human tissue macrophages (Mø). The miR-34a expression varied greatly between Mø from different tissues, correlating inversely with their capacity for AC uptake. Transient or genetic knockdown of miR-34a increased efferocytosis, whereas miR-34a overexpression decreased efferocytosis, without altering recognition of live, necrotic, or Ig-opsonized cells. The inhibitory effect of miR-34a was mediated both by reduced expression of Axl, a receptor tyrosine kinase known to recognize AC, and of the deacetylase silent information regulator T1, which had not previously been linked to efferocytosis by tissue Mø. Exposure to AC downregulated Mø miR-34a expression, resulting in a positive feedback loop that increased subsequent capacity to engulf AC. These findings demonstrate that miR-34a both specifically regulates and is regulated by efferocytosis. Given the ability of efferocytosis to polarize ingesting Mø uniquely and to reduce their host-defense functions, dynamic negative regulation by miR-34a provides one means of fine-tuning Mø behavior toward AC in specific tissue environments with differing potentials for microbial exposure.
authors.affiliation: Graduate Program in Immunology, University of Michigan Health System, Ann Arbor, MI 48109;
authors.forename: Alexandra L
authors.initials: AL
authors.lastname: McCubbrey
authors.affiliation: Division of Pulmonary & Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI 48109;
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Nelson
authors.affiliation: Research Service, VA Ann Arbor Healthcare System, Ann Arbor, MI 48105;
authors.forename: Valerie R
authors.identifier: http://orcid.org/0000-0001-6054-0592
authors.initials: VR
authors.lastname: Stolberg
authors.affiliation: Department of Neurology, University of Michigan Health System, Ann Arbor, MI 48109;
authors.forename: Pennelope K
authors.identifier: http://orcid.org/0000-0002-9677-3010
authors.initials: PK
authors.lastname: Blakely
authors.affiliation: Division of Pulmonary & Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI 48109;
authors.forename: Lisa
authors.identifier: http://orcid.org/0000-0001-5890-561X
authors.initials: L
authors.lastname: McCloskey
authors.affiliation: Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045; Department of Medicine, National Jewish Health, Denver, CO 80262; and.
authors.forename: William J
authors.identifier: http://orcid.org/0000-0002-6397-3454
authors.initials: WJ
authors.lastname: Janssen
authors.affiliation: Division of Pulmonary & Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI 48109; Research Service, VA Ann Arbor Healthcare System, Ann Arbor, MI 48105;
authors.forename: Christine M
authors.identifier: http://orcid.org/0000-0003-3548-8133
authors.initials: CM
authors.lastname: Freeman
authors.affiliation: Graduate Program in Immunology, University of Michigan Health System, Ann Arbor, MI 48109; Division of Pulmonary & Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI 48109; Pulmonary and Critical Care Medicine Section, VA Ann Arbor Healthcare System, Ann Arbor, MI 48105 jlcurtis@umich.edu.
authors.forename: Jeffrey L
authors.identifier: http://orcid.org/0000-0001-5191-4847
authors.initials: JL
authors.lastname: Curtis
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics* / Q000276:immunology; D005434:Flow Cytometry; D055785:Gene Knockdown Techniques; D006801:Humans; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000276:immunology*; D010587:Phagocytosis / Q000235:genetics* / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D056564:Sirtuin 1 / Q000276:immunology*; D014162:Transfection
chemical_list: C522425:MIRN34 microRNA, human; C551848:MIRN34a microRNA, mouse; D035683:MicroRNAs; C447939:SIRT1 protein, human; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1