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

Khmaladze, Ia; Kelkka, Tiina; Guerard, Simon; Wing, Kajsa; Pizzolla, Angela LU ; Saxena, Amit LU ; Lundqvist, Katarina LU ; Holmdahl, Meirav LU ; Kutty Selva, Nandakumar LU and Holmdahl, Rikard LU (2014) In Proceedings of the National Academy of Sciences 111(35). p.3669-3678
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... (More)
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. (Less)
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author
organization
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type
Contribution to journal
publication status
published
subject
in
Proceedings of the National Academy of Sciences
volume
111
issue
35
pages
3669 - 3678
publisher
National Acad Sciences
external identifiers
  • pmid:25136095
  • wos:000341230800014
  • scopus:84907228016
ISSN
1091-6490
DOI
10.1073/pnas.1405798111
language
English
LU publication?
yes
id
4f3afd7c-e904-40b9-8b80-b69d85b83949 (old id 4614380)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/25136095?dopt=Abstract
date added to LUP
2014-09-07 17:09:46
date last changed
2017-11-19 03:24:03
@article{4f3afd7c-e904-40b9-8b80-b69d85b83949,
  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.},
  author       = {Khmaladze, Ia and Kelkka, Tiina and Guerard, Simon and Wing, Kajsa and Pizzolla, Angela and Saxena, Amit and Lundqvist, Katarina and Holmdahl, Meirav and Kutty Selva, Nandakumar and Holmdahl, Rikard},
  issn         = {1091-6490},
  language     = {eng},
  number       = {35},
  pages        = {3669--3678},
  publisher    = {National Acad Sciences},
  series       = {Proceedings of the National Academy of Sciences},
  title        = {Mannan induces ROS-regulated, IL-17A-dependent psoriasis arthritis-like disease in mice.},
  url          = {http://dx.doi.org/10.1073/pnas.1405798111},
  volume       = {111},
  year         = {2014},
}