title: GPR43 activation enhances psoriasis-like inflammation through epidermal upregulation of IL-6 and dual oxidase 2 signaling in a murine model.
abstract: The gut is densely inhabited by commensal bacteria, which metabolize dietary fibers/undigested carbohydrates and produce short-chain fatty acids such as acetate. GPR43 is one of the receptors to sense short-chain fatty acids, and expressed in various immune and non-immune cells. Acetate/GPR43 signaling has been shown to affect various inflammatory diseases through Th17 responses and NADPH oxidase (NOX)-derived reactive oxygen species (ROS) generation. However, no study has previously explored the effects of GPR43 activation during psoriasis-like inflammation. Therefore, this study investigated the effect of acetate/phenylacetamide (GPR43 agonists) on imiquimod induced skin inflammation in mice. Mice were administered phenylacetamide/acetate followed by assessment of skin inflammation, NOXs (NOX-2, NOX-4, dual oxidases), and Th17 related signaling. Our study showed induction of epidermal GPR43 after imiquimod treatment, i.e. psoriasis-like inflammation. Acetate administration in psoriatic mice led to further increase in skin inflammation (ear thickness/myeloperoxidase activity) with concurrent increase in Th17 immune responses and epidermal dual oxidase-2 signaling. Further, topical application of GPR43 agonist, phenylacetamide led to enhanced ear thickness with concomitant epidermal IL-6 signaling as well as dual oxidase-2 upregulation which may be responsible for increased psoriasis-like inflammation. Taken together, dual oxidase-2 and IL-6 play important roles in GPR43-mediated skin inflammation. The current study suggests that GPR43 activation in psoriatic patients may lead to aggravation of psoriatic inflammation.
authors.affiliation: Department of Pharmacology & Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia. Electronic address: anadeem@ksu.edu.sa.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Nadeem
authors.affiliation: Department of Pharmacology & Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Sheikh F
authors.initials: SF
authors.lastname: Ahmad
authors.affiliation: Department of Pharmacology & Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Naif O
authors.initials: NO
authors.lastname: Al-Harbi
authors.affiliation: Industrial Engineering Department, College of Engineering, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Ahmed M
authors.initials: AM
authors.lastname: El-Sherbeeny
authors.affiliation: Department of Pharmacology & Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Mohammed M
authors.initials: MM
authors.lastname: Al-Harbi
authors.affiliation: College of Medicine, Prince Sattam Bin Abdulaziz University, Al-Kharj, Saudi Arabia.
authors.forename: Talal S
authors.initials: TS
authors.lastname: Almukhlafi
mesh_terms: D000081:Acetamides / Q000494:pharmacology; D000085:Acetates / Q000494:pharmacology; D000634:Aminoquinolines / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D004195:Disease Models, Animal; D000074623:Dual Oxidases / Q000378:metabolism*; D004817:Epidermis / Q000473:pathology*; D000077271:Imiquimod; D007249:Inflammation / Q000150:complications / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D015850:Interleukin-6 / Q000378:metabolism*; D008297:Male; D008807:Mice, Inbred BALB C; D008954:Models, Biological; D011565:Psoriasis / Q000150:complications / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D058504:Th17 Cells / Q000187:drug effects / Q000276:immunology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000081:Acetamides; D000085:Acetates; D000634:Aminoquinolines; C506481:Ffar2 protein, mouse; D015850:Interleukin-6; D043562:Receptors, G-Protein-Coupled; C030686:acetamide; D000074623:Dual Oxidases; C000614831:Duox2 protein, mouse; D000077271:Imiquimod
keywords: Dual oxidase 2; GPR43; IL-6; Psoriasis; Th17