title: Mannan induces ROS-regulated, IL-17A-dependent psoriasis arthritis-like disease in mice.
abstract: Psoriasis (Ps) and psoriasis arthritis (PsA) are poorly understood common diseases, induced by unknown environmental factors, affecting skin and articular joints. A single i.p. exposure to mannan from Saccharomyces cerevisiae induced an acute inflammation in inbred mouse strains resembling human Ps and PsA-like disease, whereas multiple injections induced a relapsing disease. Exacerbation of disease severity was observed in mice deficient for generation of reactive oxygen species (ROS). Interestingly, restoration of ROS production, specifically in macrophages, ameliorated both skin and joint disease. Neutralization of IL-17A, mainly produced by γδ T cells, completely blocked disease symptoms. Furthermore, mice depleted of granulocytes were resistant to disease development. In contrast, certain acute inflammatory mediators (C5, Fcγ receptor III, mast cells, and histamine) and adaptive immune players (αβ T and B cells) were redundant in disease induction. Hence, we propose that mannan-induced activation of macrophages leads to TNF-α secretion and stimulation of local γδ T cells secreting IL-17A. The combined action of activated macrophages and IL-17A produced in situ drives neutrophil infiltration in the epidermis and dermis of the skin, leading to disease manifestations. Thus, our finding suggests a new mechanism triggered by exposure to exogenous microbial components, such as mannan, that can induce and exacerbate Ps and PsA.
authors.affiliation: Medical Inflammation Research, Department of Biochemistry and Biophysics, Karolinska Institute, 171 77 Stockholm, Sweden;
authors.forename: Ia
authors.initials: Ia
authors.lastname: Khmaladze
authors.affiliation: Turku Doctoral Programme of Biomedical Sciences, 205 20, Turku, Finland; Medical Inflammation Research, Medicity Research Laboratory, University of Turku, 205 20, Turku, Finland; and.
authors.forename: Tiina
authors.initials: T
authors.lastname: Kelkka
authors.affiliation: Medical Inflammation Research, Department of Biochemistry and Biophysics, Karolinska Institute, 171 77 Stockholm, Sweden;
authors.forename: Simon
authors.initials: S
authors.lastname: Guerard
authors.affiliation: Medical Inflammation Research, Department of Biochemistry and Biophysics, Karolinska Institute, 171 77 Stockholm, Sweden;
authors.forename: Kajsa
authors.initials: K
authors.lastname: Wing
authors.affiliation: Medical Inflammation Research, Department of Biochemistry and Biophysics, Karolinska Institute, 171 77 Stockholm, Sweden;
authors.forename: Angela
authors.initials: A
authors.lastname: Pizzolla
authors.affiliation: Medical Inflammation Research, Department of Biochemistry and Biophysics, Karolinska Institute, 171 77 Stockholm, Sweden;
authors.forename: Amit
authors.initials: A
authors.lastname: Saxena
authors.affiliation: Department of Clinical Dermatology and Venereology, University Hospital, 221 00 Lund, Sweden.
authors.forename: Katarina
authors.initials: K
authors.lastname: Lundqvist
authors.affiliation: Department of Clinical Dermatology and Venereology, University Hospital, 221 00 Lund, Sweden.
authors.forename: Meirav
authors.initials: M
authors.lastname: Holmdahl
authors.affiliation: Medical Inflammation Research, Department of Biochemistry and Biophysics, Karolinska Institute, 171 77 Stockholm, Sweden;
authors.forename: Kutty Selva
authors.initials: KS
authors.lastname: Nandakumar
authors.affiliation: Medical Inflammation Research, Department of Biochemistry and Biophysics, Karolinska Institute, 171 77 Stockholm, Sweden; Medical Inflammation Research, Medicity Research Laboratory, University of Turku, 205 20, Turku, Finland; and rikard.holmdahl@ki.se.
authors.forename: Rikard
authors.initials: R
authors.lastname: Holmdahl
mesh_terms: D000818:Animals; D015535:Arthritis, Psoriatic / Q000139:chemically induced* / Q000276:immunology* / Q000378:metabolism; D003872:Dermatitis / Q000276:immunology / Q000473:pathology; D004195:Disease Models, Animal; D006801:Humans; D020381:Interleukin-17 / Q000276:immunology* / Q000378:metabolism; D007596:Joints / Q000276:immunology / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008351:Mannans / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009000:Monocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D019255:NADPH Oxidases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism
chemical_list: C098680:Il17a protein, mouse; D020381:Interleukin-17; D008351:Mannans; D017382:Reactive Oxygen Species; D016692:Receptors, Antigen, T-Cell, gamma-delta; D014409:Tumor Necrosis Factor-alpha; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1
keywords: Ncf1; animal model; autoimmune disease