Mechanisms of age-dependent loss of resistance to allergic contact dermatitis in mice with innate immune system defects
Final Report Abstract
Mice lacking TLR4/IL-12Rβ2 or TLR2/4 are resistant to contact hypersensitivity (CHS), a T cell-mediated inflammatory skin disease, at the age of 8 weeks. At the age of 18-20 weeks this resistance is lost. We could show that other mouse strains with different defects in the innate immune system which is responsible for the inflammation also age-dependently lose their resistance to CHS. In contrast to our expectation also the young resistant mice show an infiltration of monocytes and neutrophils into the skin following allergen application. However, only the old mice are able to mount an allergen specific T cell response. A difference in skin barrier was not detected. The analysis of the state of inflammation of the old animals failed to reveal and age-dependent basal inflammation that could explain the sensitization to contact allergens. Inflammation is induced only after allergen contact. One explanation for the loss of resistance could be the increase in adipose tissue, which is an important source for inflammatory mediators, e.g. in obesity or associated with age. Only the old animals showed an infiltration of CD45+ T cells in the adipose tissue and produced a factor in the adipose tissue that could explain the lack of a T cell response in young animals. We are in the process of addressing this question experimentally. This may be a key factor explaining the age-dependent difference between resistance and susceptibility. In the course of the project we identified interesting, in part novel aspects of the inflammatory process in CHS. The observed transient keratinocyte hyperproliferation goes along with an upregulation of the keratins 5, 17 and, most prominently, 16, as in psoriasis. Neutrophils infiltrate the epidermis and form pustules and microabscesses eventually damaging the skin barrier. Simultaneously, genes for tissue repair are upregulated. Serum amyloid deposition and upregulation of FABP5 are observed. All of these factors contribute to skin inflammation, keratinocyte hyperproliferation and tissue repair. This project shows that there are alternative mechanisms of inflammation associated with adipose tissue that allow for induction of CHS independent of the innate immune system. In a related project, we were able to verify this by feeding young resistant mice a high fat diet showing the loss of resistance to CHS 1. We are currently investigating the underlying mechanisms. Our results underline the essential role of inflammation in the activation of immune responses und demonstrate that the mechanisms of inflammation are strongly influenced by age and diet. This important observation must be taken into account in research involving animal experiments. The fact that an alternative, adipose tissue-associated and TLR2/4-independent mechanisms enables CHS in old mice, shows how important the exact knowledge on inflammatory mechanisms in diseases is, since this decides whether a therapy is successful or not. This is similar for disease endotypes e.g. of atopic dermatitis or asthma.
Publications
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Feeding of a fat‐enriched diet causes the loss of resistance to contact hypersensitivity. Contact Dermatitis, 85(4), 398-406.
Rühl‐Muth, Anne‐Catherine; Maler, Mareike D.; Esser, Philipp R. & Martin, Stefan F.
