Nitric Oxide Engages an Anti-inflammatory Feedback Loop Mediated by Peroxiredoxin 5 in Phagocytes

Daniel B Graham; Guadalupe J Jasso; Amanda Mok; Gautam Goel; Aylwin C Y Ng; Raivo Kolde; Mukund Varma; John G Doench; David E Root; Clary B Clish; Steven A Carr; Ramnik J Xavier

doi:10.1016/j.celrep.2018.06.081

Nitric Oxide Engages an Anti-inflammatory Feedback Loop Mediated by Peroxiredoxin 5 in Phagocytes

Cell Rep. 2018 Jul 24;24(4):838-850. doi: 10.1016/j.celrep.2018.06.081.

Authors

Affiliations

¹ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Molecular Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02114, USA; Center for Microbiome Informatics and Therapeutics, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Electronic address: dgraham@broadinstitute.org.
² Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Harvard Medical School, Boston, MA 02114, USA.
³ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁴ Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA 02114, USA.
⁵ Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02114, USA.
⁶ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Molecular Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02114, USA; Center for Microbiome Informatics and Therapeutics, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA 02114, USA. Electronic address: xavier@molbio.mgh.harvard.edu.

Abstract

Phagocyte microbiocidal mechanisms and inflammatory cytokine production are temporally coordinated, although their respective interdependencies remain incompletely understood. Here, we identify a nitric-oxide-mediated antioxidant response as a negative feedback regulator of inflammatory cytokine production in phagocytes. In this context, Keap1 functions as a cellular redox sensor that responds to elevated reactive nitrogen intermediates by eliciting an adaptive transcriptional program controlled by Nrf2 and comprised of antioxidant genes, including Prdx5. We demonstrate that engaging the antioxidant response is sufficient to suppress Toll-like receptor (TLR)-induced cytokine production in dendritic cells and that Prdx5 is required for attenuation of inflammatory cytokine production. Collectively, these findings delineate the reciprocal regulation of inflammation and cellular redox systems in myeloid cells.

Keywords: Keap1; Nos2; Prdx5; antioxidant response; cytokines; dendritic cells; nitric oxide.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Bone Marrow Cells / metabolism
Cytokines / biosynthesis
Feedback, Physiological
HEK293 Cells
Humans
Mice
Mice, Inbred C57BL
Nitric Oxide / biosynthesis
Nitric Oxide / metabolism*
Peroxiredoxins / metabolism*
Phagocytes / metabolism*
Signal Transduction

Substances

Cytokines
Nitric Oxide
Peroxiredoxins
Prdx5 protein, mouse

Abstract

Publication types

MeSH terms

Substances

Grants and funding