Nitric Oxide-Releasing Nanoparticles Prevent Propionibacterium acnes-Induced Inflammation by Both Clearing the Organism and Inhibiting Microbial Stimulation of the Innate Immune Response

J Invest Dermatol. 2015 Nov;135(11):2723-2731. doi: 10.1038/jid.2015.277. Epub 2015 Jul 14.

Abstract

Propionibacterium acnes induction of IL-1 cytokines through the NLRP3 (NLR, nucleotide oligomerization domain-like receptor) inflammasome was recently highlighted as a dominant etiological factor for acne vulgaris. Therefore, therapeutics targeting both the stimulus and the cascade would be ideal. Nitric oxide (NO), a potent biological messenger, has documented broad-spectrum antimicrobial and immunomodulatory properties. To harness these characteristics to target acne, we used an established nanotechnology capable of generating/releasing NO over time (NO-np). P. acnes was found to be highly sensitive to all concentrations of NO-np tested, although human keratinocyte, monocyte, and embryonic zebra fish assays revealed no cytotoxicity. NO-np significantly suppressed IL-1β, tumor necrosis factor-α (TNF-α), IL-8, and IL-6 from human monocytes, and IL-8 and IL-6 from human keratinocytes, respectively. Importantly, silencing of NLRP3 expression by small interfering RNA did not limit NO-np inhibition of IL-1 β secretion from monocytes, and neither TNF-α nor IL-6 secretion, nor inhibition by NO-np was found to be dependent on this pathway. The observed mechanism by which NO-np impacts IL-1β secretion was through inhibition of caspase-1 and IL-1β gene expression. Together, these data suggest that NO-np can effectively prevent P. acnes-induced inflammation by both clearing the organism and inhibiting microbial stimulation of the innate immune response.

Publication types

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

MeSH terms

  • Animals
  • Caspase 1 / metabolism
  • Cells, Cultured
  • Disease Models, Animal
  • Humans
  • Immunity, Innate / immunology*
  • Immunity, Innate / physiology*
  • Inflammation / immunology
  • Inflammation / metabolism
  • Interleukin-1 / immunology*
  • Interleukin-1 / metabolism
  • Keratinocytes / cytology
  • Keratinocytes / immunology
  • Leukocytes, Mononuclear / immunology
  • Leukocytes, Mononuclear / metabolism
  • Male
  • Microscopy, Electron / methods
  • Nanoparticles / metabolism
  • Nitric Oxide / metabolism*
  • Propionibacterium acnes / immunology*
  • Propionibacterium acnes / metabolism
  • RNA, Small Interfering / metabolism
  • Rats
  • Rats, Sprague-Dawley

Substances

  • Interleukin-1
  • RNA, Small Interfering
  • Nitric Oxide
  • Caspase 1