Yuliya Skabytska

The role of innate immune signaling in the pathogenesis of atopic dermatitis and consequences for treatments

The skin is the largest organ at the interface between the environment and the host. Consequently, the skin plays a central role in mounting effective host defense. In addition to pathogens, the microbiota and the host immune system are in permanent contact and communication via the skin. Consequences of this permanent interaction are a unique and partly symbiotic relationship, a tight interdependence between these partners, and also a functional “setting the clock,” in which, in the healthy steady state, an induction of protective responses to pathogens is guaranteed. At the same time, commensal microbes contribute to the alertness of the immune system and to the maintenance of immune tolerance. Atopic dermatitis (AD) is a chronic inflammatory skin disease based on a complex genetic trait with defects in cutaneous barrier, in stabilizing skin integrity. Most of AD patients develop deviated innate and adaptive immune responses. As a result, increased susceptibility to cutaneous infection is found in AD patients, and the interactions between these microbes and the skin participate in the development of chronic cutaneous inflammation. The role of the adaptive immune system was characterized in much detail, less though the contribution of innate immunity to AD pathogenesis. It is rather recent evidence that demonstrates a dominant role of components of the innate immune system not only for protecting from microbial invasion but also by orchestrating chronic skin inflammation. In this review we discuss the role of innate immune signaling and consecutive immune networks important for the pathogenesis and management of AD.

How the innate immune system trains immunity: lessons from studying atopic dermatitis and cutaneous bacteria

The skin is the largest organ at the interface between environment and host. It plays a major protective role against pathogens as physical barrier, as site of first recognition, and as orchestrator of consecutive immune responses. In this process, immunological crosstalk between skin‐resident and immune cells is required, and fixed innate immune responses were previously believed to orchestrate adaptive immunity of B and T lymphocytes. Today, we understand that diverse qualities of immune responses to different microbes need to be regulated by also varying responses at the level of first microbe recognition through receptors of the innate immune system. Only fine‐tuning of the innate immune system allows for the orchestration of immune responses to the microbiota in the absence of inflammation as well as to pathogens in the context of protective responses including inflammation. Understanding how innate immunity precisely adapts is also important for diseases such as atopic dermatitis (AD) with chronic inflammation. In this review, we present data on how the innate immune system actually fine‐tunes its responses with special focus on the immunological consequences of cutaneous innate immune sensing through TLR2. These new insights are highly relevant for understanding microbiota‐associated state of health, immune defense, and the pathogenesis underlying chronic cutaneous inflammation as seen in AD.

Evidence for biochemical barrier restoration: Topical solenopsin analogs improve inflammation and acanthosis in the KC-Tie2 mouse model of psoriasis.

Psoriasis is a chronic inflammatory skin disease affecting 2.5–6 million patients in the United States. The cause of psoriasis remains unknown. Previous human and animal studies suggest that patients with a susceptible genetic background and some stimulus, such as barrier disruption, leads to a coordinated signaling events involving cytokines between keratinocytes, endothelial cells, T cells, macrophages and dendritic cells. Ceramides are endogenous skin lipids essential for maintaining skin barrier function and loss of ceramides may underlie inflammatory and premalignant skin. Ceramides act as a double-edged sword, promoting normal skin homeostasis in the native state, but can be metabolized to sphingosine-1-phosphate (S1P), linked to inflammation and tumorigenesis. To overcome this difficulty, we synthesized solenopsin analogs which biochemically act as ceramides, but cannot be metabolized to S1P. We assess their in vivo bioactivity in a well-established mouse model of psoriasis, the KC-Tie2 mouse. Topical solenopsin derivatives normalized cutaneous hyperplasia in this model, decreased T cell infiltration, interleukin (IL)-22 transcription, and reversed the upregulation of calprotectin and Toll-like receptor (TLR) 4 in inflamed skin. Finally, they stimulated interleukin (IL)-12 production in skin dendritic cells. Thus suggesting barrier restoration has both a biochemical and physical component, and both are necessary for optimal barrier restoration.

Staphylococcus epidermidis Sets Things Right Again.

Commensal cutaneous bacteria are believed to play a role in skin homeostasis, possibly by counteracting the effects of pathogenic inflammation. In this issue, Xia et al. show that Staphylococcus epidermidis is involved in the regulation of Propionibacterium acnes-induced inflammation. Staphylococcal lipoteichoic acid induces miR-143, which in turn inhibits toll-like receptor 2 mRNA to decrease toll-like receptor 2 protein and consequently suppresses P. acnes-induced proinflammatory cytokines.

Induction of IL‐10‐balanced immune profiles following exposure to LTA from Staphylococcus epidermidis

Staphylococcus epidermidis colonises human skin without apparent inflammation, but a dominance of S. epidermidis and S. aureus is characteristic of cutaneous microbial dysbiosis in atopic dermatitis (AD). While S. aureus can trigger AD, the role of S. epidermidis is less understood. We characterised consequences of innate immune sensing of lipoteichoic acid (LTA) preparations derived from S. epidermidis (epi‐LTA) or S. aureus (aureus‐LTA). Therefore, dendritic cell (DC) activation and consecutive priming of antigen‐specific T cells following exposure of DC to epi‐LTA or aureus‐LTA were investigated. Mimicking acute AD, exposure of DC to IL‐4 and LTAs was analysed. Exposure to epi‐LTA or aureus‐LTA activated human immune cells and murine dendritic cells (DCs) via TLR2/MyD88, however, resulting in divergent immune profiles. Differences between LTAs were significant for IL‐6, IL‐12p40 and IL‐12p70 but not for IL‐10, which was best reflected by the IL‐12p70‐to‐IL‐10 ratio being IL‐10‐balanced for epi‐LTA but pro‐inflammatory for aureus‐LTA. LTA‐exposed DCs activated CD4+ T cells; however, while T‐cell‐derived IL‐10 was equivalent between LTAs, IFN‐γ and IL‐17 were significantly higher for aureus‐LTA. Mimicking acute AD by exposing DCs to IL‐4 and LTAs revealed that IL‐4 significantly and uniformly suppressed epi‐LTA‐induced cytokine production, keeping the IL‐12p70‐to‐IL‐10 ratio balanced. In contrast, exposure of DCs to aureus‐LTA and IL‐4 enhanced IL‐12p70 but suppressed IL‐10 levels, further unbalancing the IL‐12p70‐to‐IL‐10 ratio. These data demonstrate opposing immune consequences following exposure to staphylococcal LTAs. Epi‐LTA induced IL‐10‐balanced, aureus‐LTA pro‐inflammatory immune profiles.

Biodiversität und Immuntoleranz in der Allergologie

ZusammenfassungHintergrundUnser Immunsystem ist in der Lage, eine Vielzahl von Substanzen und Organismen aus der Umwelt zu detektieren und in unterschiedlichster Weise darauf zu reagieren. Dies umfasst einerseits Abwehrreaktionen gegen Pathogene und andererseits Immuntoleranz in Form von immunregulatorischen Reaktionen, die zur Terminierung von Immunantworten oder zum Tolerieren harmloser und körpereigener Substanzen führen. Dabei ist die Ausbildung von Immuntoleranz ein aktiver Prozess, der entscheidend durch die Interaktion mit Mikrobiota und Umweltbestandteilen geprägt und vornehmlich über regulatorische T-Zellen vermittelt wird.MethodenDiese Arbeit ist ein Überblick ausgewählter, wissenschaftlicher Artikel und wurde mit Recherchen in Pubmed, Fachdatenbanken und Leitlinien erstellt.ErgebnisseEntsprechend der Diversitätshypothese wird heute eine Exposition im frühen Kindesalter gegenüber einer breiten Biodiversität als risikomindernd für die Entwicklung allergischer Erkrankungen betrachtet.SchlussfolgerungDaraus leitet sich für die Allergologie als potenzielles Konzept die Induktion von Toleranz nicht nur als präventive, sondern auch als therapeutische Maßnahme bei Erkrankungen des atopischen Formenkreises ab.