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Regulation of Monocyte Functional Heterogeneity by miR-146a and Relb

Etzrodt, Martin and Cortez-Retamozo, Virna and Newton, Andita and Zhao, Jimmy and Ng, Aylwin and Wildgruber, Moritz and Romero, Pedro and Wurdinger, Thomas and Xavier, Ramnik and Geissmann, Frederic and Meylan, Etienne and Nahrendorf, Matthias and Swirski, Filip K. and Baltimore, David and Weissleder, Ralph and Pittet, Mikael J. (2012) Regulation of Monocyte Functional Heterogeneity by miR-146a and Relb. Cell Reports, 1 (4). pp. 317-324. ISSN 2211-1247. PMCID PMC3334310.

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Monocytes serve as a central defense system against infection and injury but can also promote pathological inflammatory responses. Considering the evidence that monocytes exist in at least two subsets committed to divergent functions, we investigated whether distinct factors regulate the balance between monocyte subset responses in vivo. We identified a microRNA (miRNA), miR-146a, which is differentially regulated both in mouse (Ly-6C^(hi)/Ly-6C^(lo)) and human (CD14^(hi)/CD14^(lo)CD16^+) monocyte subsets. The single miRNA controlled the amplitude of the Ly-6C^(hi) monocyte response during inflammatory challenge whereas it did not affect Ly-6C^(lo) cells. miR-146a-mediated regulation was cell-intrinsic and depended on Relb, a member of the noncanonical NF-κB/Rel family, which we identified as a direct miR-146a target. These observations not only provide mechanistic insights into the molecular events that regulate responses mediated by committed monocyte precursor populations but also identify targets for manipulating Ly-6C^(hi) monocyte responses while sparing Ly-6C^(lo) monocyte activity.

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Baltimore, David0000-0001-8723-8190
Additional Information:© 2012 The Authors. Received: October 12, 2011. Revised: February 14, 2012. Accepted: February 24, 2012. Published online: April 5, 2012. This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 Unported License (CC-BY-NC-ND; legalcode). The authors thank Mike Waring, Andrew Cosgrove, and Adam Chicoine (Ragon Institute of MGH, MIT, and Harvard) for cell sorting; Borja Saez (Harvard Medical School), Patrick Stern, and David Feldser (MIT) for help with retroviral gene transfer. Charles Vanderburg and Anna Krichevsky (Harvard Medical School) for help with analytical RNA techniques; and Yoshiko Iwamoto and Joshua Dunham (MGH Center for Systems Biology) for help with immunofluorescence staining and imaging. M.E. is part of the International PhD program ‘‘Cancer and Immunology’’ at the University of Lausanne, Switzerland and was supported by the American Association for Cancer Research Centennial Predoctoral Fellowship and the Boehringer Ingelheim Fonds. This work was supported in part by National Institutes of Health grants NIH-R01 AI084880 (to M.J.P.) and P30 DK043351 (to M.J.P. and R.X.). D.B. is a director and chairman of the scientific advisory board of Regulus Therapeutics, a biotech company developing miRNA-based drugs.
Funding AgencyGrant Number
American Association for Cancer ResearchUNSPECIFIED
Boehringer Ingelheim FondsUNSPECIFIED
NIHR01 AI084880
NIHP30 DK043351
Issue or Number:4
PubMed Central ID:PMC3334310
Record Number:CaltechAUTHORS:20121116-144353588
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:35523
Deposited By: Ruth Sustaita
Deposited On:16 Nov 2012 23:29
Last Modified:26 Nov 2019 20:10

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