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Mannan induces ROS-regulated, IL-17A-dependent psoriasis arthritis-like disease in mice
Ia Khmaladze1, Tiina Kelkka2, Simon Guerard1
1Medical Inflammation Research, Department of Biochemistry and Biophysics, Karolinska Institute, 171 77 Stockholm, Sweden;
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.
Insights
Mannan from Saccharomyces cerevisiae triggers psoriasis and psoriatic arthritis-like disease in mice. Reactive oxygen species (ROS) and IL-17A are key factors, with macrophages and γδ T cells playing crucial roles.
Area of Science:
- Immunology
- Dermatology
- Rheumatology
Background:
- Psoriasis (Ps) and psoriatic arthritis (PsA) are common, poorly understood diseases potentially triggered by environmental factors.
- The specific mechanisms underlying Ps and PsA pathogenesis remain largely unknown.
Purpose of the Study:
- To investigate the role of Saccharomyces cerevisiae mannan in inducing Ps and PsA-like disease in mice.
- To elucidate the immune pathways involved in mannan-induced skin and joint inflammation.
Main Methods:
- Induction of Ps and PsA-like disease in mice via intraperitoneal mannan exposure.
- Assessment of disease severity in mice with altered reactive oxygen species (ROS) production, granulocyte depletion, or targeted neutralization of IL-17A.
Main Results:
- Single mannan exposure induced acute, while multiple exposures induced relapsing, Ps and PsA-like disease.
- Deficiency in ROS generation exacerbated disease; ROS restoration in macrophages ameliorated symptoms.
- IL-17A neutralization completely blocked disease, and granulocyte depletion conferred resistance.
- Certain inflammatory mediators and adaptive immune cells were found to be non-essential for disease induction.
Conclusions:
- Mannan exposure activates macrophages, leading to TNF-α secretion and subsequent stimulation of γδ T cells to produce IL-17A.
- The interplay between macrophages and IL-17A drives neutrophil infiltration, causing skin and joint manifestations.
- This study reveals a novel mechanism where microbial components like mannan can initiate and worsen Ps and PsA.
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