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.

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