Dataset Information

Spontaneous atopic dermatitis in mice with a defective skin barrier is independent of ILC2 and mediated by IL-1?.

ABSTRACT:

Background

Atopic dermatitis (AD) is one of the most common skin diseases with a multifactorial etiology. Mutations leading to loss of skin barrier function are associated with the development of AD with group 2 innate lymphoid cells (ILC2) promoting acute skin inflammation. Filaggrin-mutant (Flg^ft/ft ) mice develop spontaneous skin inflammation accompanied by an increase in skin ILC2 numbers, IL-1? production, and other cytokines recapitulating human AD. Here, we investigated the role of ILC2, effector cytokines, inflammasome activation, and mast cell function on the development of chronic AD-like inflammation in mice.

Methods

Mice with a frameshift mutation in the filaggrin gene develop spontaneous dermatitis. Flg^ft/ft mice were crossed to cell- or cytokine-deficient mouse strains, or bred under germ-free conditions. Skin inflammation was scored, and microbiome composition was analyzed. Skin protein expression was measured by multiplex immunoassay. Infiltrating cells were analyzed by flow cytometry.

Results

Wild-type and Flg^ft/ft mice significantly differ in their microbiome composition. Furthermore, mutant mice do not develop skin inflammation under germ-free conditions. ILC2 deficiency did not ameliorate chronic dermatitis in Flg^ft/ft mice, which was also independent of IL-4, IL-5, IL-9, IL-13, IL-17A, and IL-22. Inflammation was independent of NLRP3 inflammasome activation but required IL-1? and IL-1R1-signaling. Mechanistically, IL-1? promoted hyperactivation of IL-1R1-expressing mast cells. Treatment with anti-IL-1?-antibody alleviated dermatitis exacerbation, while antibiotic intervention ameliorated dermatitis in neonatal mice but not in adults with established inflammation.

Conclusions

In summary, we identified a critical role for the microbiome and IL-1? mediating chronic inflammation in mice with an impaired skin barrier.

SUBMITTER: Schwartz C

PROVIDER: S-EPMC6850072 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Publications

Spontaneous atopic dermatitis in mice with a defective skin barrier is independent of ILC2 and mediated by IL-1β.

Schwartz Christian C Moran Tara T Saunders Sean P SP Kaszlikowska Agnieszka A Floudas Achilleas A Bom Joana J Nunez Gabriel G Iwakura Yoichiro Y O'Neill Luke L Irvine Alan D AD McKenzie Andrew N J ANJ Ogg Graham G Walsh Patrick T PT Demengeot Jocelyne J Fallon Padraic G PG

Allergy 20190429 10

<h4>Background</h4>Atopic dermatitis (AD) is one of the most common skin diseases with a multifactorial etiology. Mutations leading to loss of skin barrier function are associated with the development of AD with group 2 innate lymphoid cells (ILC2) promoting acute skin inflammation. Filaggrin-mutant (Flg<sup>ft/ft</sup> ) mice develop spontaneous skin inflammation accompanied by an increase in skin ILC2 numbers, IL-1β production, and other cytokines recapitulating human AD. Here, we investigated ...[more]

PMID: 30937919

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Project description:Atopic dermatitis (AD) is a widely spread cutaneous chronic disease characterised by sensitive reactions (eg. eczema) to normally innocuous elements. Although relatively little is understood about its underlying mechanisms due to its complexity, skin barrier dysfunction has been recognised as a key factor in the development of AD. Skin barrier homeostasis requires tight control of the activity of proteases, called kallikreins (KLKs), whose activity is regulated by a complex network of protein interactions that remains poorly understood despite its pathological importance. Characteristic symptoms of AD include the outbreak of inflammation triggered by external (eg. mechanical and chemical) stimulus and the persistence and aggravation of inflammation even if the initial stimulus disappears. These characteristic symptoms, together with some experimental data, suggest the presence of positive feedback regulation for KLK activity by inflammatory signals. We developed simple mathematical models for the KLK activation system to study the effects of feedback loops and carried out bifurcation analysis to investigate the model behaviours corresponding to inflammation caused by external stimulus. The model analysis confirmed that the hypothesised core model mechanisms capture the essence of inflammation outbreak by a defective skin barrier. Our models predicted the outbreaks of inflammation at weaker stimulus and its longer persistence in AD patients compared to healthy control. We also proposed a novel quantitative indicator for inflammation level by applying principal component analysis to microarray data. The model analysis reproduced qualitative AD characteristics revealed by this indicator. Our results strongly implicate the presence and importance of feedback mechanisms in KLK activity regulation. We further proposed future experiments that may provide informative data to enhance the system-level understanding on the regulatory mechanisms of skin barrier in AD and healthy individuals.