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Proc Natl Acad Sci U S A. 2014 Sep 2;111(35):E3669-78. doi: 10.1073/pnas.1405798111. Epub 2014 Aug 18.

Mannan induces ROS-regulated, IL-17A-dependent psoriasis arthritis-like disease in mice.

Author information

1
Medical Inflammation Research, Department of Biochemistry and Biophysics, Karolinska Institute, 171 77 Stockholm, Sweden;
2
Turku Doctoral Programme of Biomedical Sciences, 205 20, Turku, Finland; Medical Inflammation Research, Medicity Research Laboratory, University of Turku, 205 20, Turku, Finland; and.
3
Department of Clinical Dermatology and Venereology, University Hospital, 221 00 Lund, Sweden.
4
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.

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.

KEYWORDS:

Ncf1; animal model; autoimmune disease

PMID:
25136095
PMCID:
PMC4156700
DOI:
10.1073/pnas.1405798111
[Indexed for MEDLINE]
Free PMC Article

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