UV-mediierte Regulation antimikrobieller Peptide
Zusammenfassung der Projektergebnisse
Despite the well-known immunosuppressive effects of ultraviolet radiation (UV) bacterial superinfections are rather rarely observed upon UV exposure. This may be due to the induction of the release of antimicrobial peptides (AMP) from keratinocytes by UV. Since UV disturbs the epidermal barrier the induction of AMP may be regarded as a protective mechanism preventing the invasion of microbial pathogens into the skin after UV exposure. Since the same UV doses inhibit the induction of T-cell driven immune reactions we hypothesized that this may be also a protective mechanisms preventing the sensitization to contact allergens which can easier penetrate barrier disrupted epidermis. Accordingly, the murine AMP β-defensin-14 (mBD14) inhibited the induction of contact hypersensitivity in mice. This inhibition was due to the generation of antigen-specific regulatory T cells which behaved in a similar fashion as Treg induced by UV. Through this capacity, mBD14 may protect the host from microbial attacks on the one hand, but tame T-cell-driven reactions on the other hand, thereby enabling an antimicrobial defense without collateral damage by the adaptive immune system. Because of their antigen-specificity UV-induced Treg harbor potential for the therapy of (auto)immune diseases. However, any UV exposure is associated with the induction of DNA damage which on the long term may contribute to photocarcinogenesis. Hence, we regarded AMPs as an alternative route to induce similar Treg. To expand on this, it was tested whether mBD-14-induced Treg exert suppressive activity also in other immunological models than contact hypersensitivity. We utilized experimental allergic autoimmune encephalomyelitis which is regarded as a model for multiple sclerosis. Injection of mBD14 into mice before immunization with myelin oligodendrocyte glycoprotein caused amelioration of the disease with less central nervous system inflammation, decreased levels of pro-inflammatory cytokines and cytotoxic T cells. The beneficial effect was due to Foxp3+ Treg since it was lost upon in vivo depletion of Treg. mBD14 appears to switch non-regulatory T cells in a regulatory phenotype which exerts suppressive capacities. Thus, defensins seem to target primarily T cells and not antigenpresenting cells which are modulated by ligands of the arylhydrocarbon receptor, which also induce immunosuppressive effects comparable to UVR. Even more importantly, mBD14 also acted in a therapeutic setting, since injection of mBD14 into mice with clinical features of EAE reduced the clinical score significantly. To test whether the immunosuppressive features of AMPs also apply for the human system, the human AMP βdefensin-3 (hBD3) which is the human orthologue of mBD14 was used. hBD3 induced in vitro Treg-specific markers in CD4+CD25−T cells, shifting these non-regulatory cells into a regulatory phenotype with suppressive features. Taken together, this project identified with the immunosuppressive activity a new feature of AMPs. Furthermore, AMPs appear to be promising candidates for the therapy of (auto)immune diseases since they induced antigen-specific Treg in a similar fashion as UV but without inducing DNA damage. In addition, AMPs appear to inhibit not only the induction but also the elicitation phase of immune reactions, implying that AMPs may not only work in a preventive but also therapeutic setting. This has to be confirmed in future studies.
Projektbezogene Publikationen (Auswahl)
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(2015). Activation of the Arylhydrocarbon Receptor Causes Immunosuppression Primarily by Modulating Dendritic Cells. J Invest Dermatol 135:435-44
Bruhs A, Haarmann-Stemmann T, Frauenstein K, Krutmann J, Schwarz T, Schwarz A
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(2016). Prevention and mitigation of experimental autoimmune encephalomyelitis by murine β-defensins via induction of regulatory T cells. J Invest Dermatol 136:173-81
Bruhs A, Schwarz T, Schwarz A
