title: TLR-7 agonist attenuates airway reactivity and inflammation through Nrf2-mediated antioxidant protection in a murine model of allergic asthma.
abstract: Toll-like receptors (TLRs) through innate immune system recognize pathogen associated molecular patterns and play an important role in host defense against bacteria, fungi and viruses. TLR-7 is responsible for sensing single stranded nucleic acids of viruses but its activation has been shown to be protective in mouse models of asthma. The NADPH oxidase (NOX) enzymes family mainly produces reactive oxygen species (ROS) in the lung and is involved in regulation of airway inflammation in response to TLRs activation. However, NOX-4 mediated signaling in response to TLR-7 activation in a mouse model of allergic asthma has not been explored previously. Therefore, this study investigated the role TLR-7 activation and downstream oxidant-antioxidant signaling in a murine model of asthma. Mice were sensitized with ovalbumin (OVA) intraperitoneally and treated with TLR-7 agonist, resiquimod (RSQ) intranasally before each OVA challenge from days 14 to 16. Mice were then assessed for airway reactivity, inflammation, and NOX-4 and nuclear factor E2-related factor 2 (Nrf2) related signaling [inducible nitric oxide synthase (iNOS), nitrotyrosine, lipid peroxides and copper/zinc superoxide dismutase (Cu/Zn SOD)]. Treatment with RSQ reduced allergen induced airway reactivity and inflammation. This was paralleled by a decrease in ROS which was due to induction of Nrf2 and Cu/Zn SOD in RSQ treated group. Inhibition of MyD88 reversed RSQ-mediated protective effects on airway reactivity/inflammation due to reduction in Nrf2 signaling. SOD inhibition produced effects similar to MyD88 inhibition. The current study suggests that TLR-7 agonist is beneficial and may be developed into a therapeutic option in allergic asthma.
authors: Department of Pharmacology & Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia. Electronic address: anadeem@ksu.edu.sa.
authors: Ahmed
authors: A
authors: Nadeem
authors: Amity Institute of Biotechnology, Amity University, Noida, India.
authors: Nahid
authors: N
authors: Siddiqui
authors: Department of Pharmacology & Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
authors: Naif O
authors: NO
authors: Al-Harbi
authors: Department of Pharmacology & Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
authors: Mohammed M
authors: MM
authors: Al-Harbi
authors: Department of Pharmacology & Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
authors: Sheikh F
authors: SF
authors: Ahmad
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D001249:Asthma / Q000188:drug therapy* / Q000378:metabolism; D018893:Bronchoalveolar Lavage; D007093:Imidazoles / Q000494:pharmacology; D015151:Immunoblotting; D007249:Inflammation / Q000188:drug therapy* / Q000378:metabolism; D008054:Lipid Peroxides / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000819:agonists*; D051379:Mice; D008807:Mice, Inbred BALB C; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D013482:Superoxide Dismutase / Q000378:metabolism; D051199:Toll-Like Receptor 7 / Q000819:agonists*; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D000975:Antioxidants; D007093:Imidazoles; D008054:Lipid Peroxides; D008562:Membrane Glycoproteins; D051267:NF-E2-Related Factor 2; D017382:Reactive Oxygen Species; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7; C002744:3-nitrotyrosine; D014443:Tyrosine; D013482:Superoxide Dismutase; C402365:resiquimod
keywords: Airway inflammation; Cu/Zn SOD; NADPH oxidase; Nrf2; TLR-7 agonist