Regulation of Monocyte Functional Heterogeneity by miR-146a and Relb
Martin Etzrodt,
Virna Cortez-Retamozo,
Andita Newton,
Jimmy Zhao,
Aylwin Ng,
Moritz Wildgruber,
Pedro Romero,
Thomas Wurdinger,
Ramnik Xavier,
Frederic Geissmann,
Etienne Meylan,
Matthias Nahrendorf,
Filip K. Swirski,
David Baltimore,
Ralph Weissleder,
Mikael J. Pittet
Affiliations
Martin Etzrodt
Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
Virna Cortez-Retamozo
Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
Andita Newton
Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
Jimmy Zhao
Division of Biology, California Institute of Technology, Pasadena, CA 91125, USA
Aylwin Ng
Center for Computational and Integrative Biology and Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
Moritz Wildgruber
Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
Pedro Romero
Ludwig Center for Cancer Research, CH-1005 Lausanne, Switzerland
Thomas Wurdinger
Cancer Center Amsterdam, VU University Medical Center, Amsterdam 1080, The Netherlands
Ramnik Xavier
Center for Computational and Integrative Biology and Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
Frederic Geissmann
Centre for Molecular and Cellular Biology of Inflammation, King's College London, SE1 1UL London, UK
Etienne Meylan
Swiss Institute for Experimental Cancer Research, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland
Matthias Nahrendorf
Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
Filip K. Swirski
Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
David Baltimore
Division of Biology, California Institute of Technology, Pasadena, CA 91125, USA
Ralph Weissleder
Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
Mikael J. Pittet
Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
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-6Chi/Ly-6Clo) and human (CD14hi/CD14loCD16+) monocyte subsets. The single miRNA controlled the amplitude of the Ly-6Chi monocyte response during inflammatory challenge whereas it did not affect Ly-6Clo 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-6Chi monocyte responses while sparing Ly-6Clo monocyte activity.
