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

• Published in: Journal of investigative dermatology Vol. 135; no. 11; pp. 2723 - 2731
• Main Authors: Qin, Min, Landriscina, Angelo, Rosen, Jamie M., Wei, Gabrielle, Kao, Stephanie, Olcott, William, Agak, George W., Paz, Karin B., Bonventre, Josephine, Clendaniel, Alicea, Harper, Stacey, Adler, Brandon L., Krausz, Aimee E., Friedman, Joel M., Nosanchuk, Joshua D., Kim, Jenny, Friedman, Adam J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-11-2015; Elsevier Limited
• Subjects: Animals; Caspase 1 - metabolism; Cells, Cultured; Danio rerio; 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; Propionibacterium acnes; Propionibacterium acnes - immunology; Propionibacterium acnes - metabolism; Rats; Rats, Sprague-Dawley; RNA, Small Interfering - metabolism
• ISSN: 0022-202X; 1523-1747
• DOI: 10.1038/jid.2015.277

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.