CD201+ fascia progenitors choreograph injury repair.

Optimal tissue recovery and organismal survival are achieved by spatiotemporal tuning of tissue inflammation, contraction and scar formation1. Here we identify a multipotent fibroblast progenitor marked by CD201 expression in the fascia, the deepest connective tissue layer of the skin. Using skin injury models in mice, single-cell transcriptomics and genetic lineage tracing, ablation and gene deletion models, we demonstrate that CD201+ progenitors control the pace of wound healing by generating multiple specialized cell types, from proinflammatory fibroblasts to myofibroblasts, in a spatiotemporally tuned sequence. We identified retinoic acid and hypoxia signalling as the entry checkpoints into proinflammatory and myofibroblast states. Modulating CD201+ progenitor differentiation impaired the spatiotemporal appearances of fibroblasts and chronically delayed wound healing. The discovery of proinflammatory and myofibroblast progenitors and their differentiation pathways provide a new roadmap to understand and clinically treat impaired wound healing.

Patch repair of deep wounds by mobilized fascia.

Mammals form scars to quickly seal wounds and ensure survival by an incompletely understood mechanism1-5. Here we show that skin scars originate from prefabricated matrix in the subcutaneous fascia. Fate mapping and live imaging revealed that fascia fibroblasts rise to the skin surface after wounding, dragging their surrounding extracellular jelly-like matrix, including embedded blood vessels, macrophages and peripheral nerves, to form the provisional matrix. Genetic ablation of fascia fibroblasts prevented matrix from homing into wounds and resulted in defective scars, whereas placing an impermeable film beneath the skin-preventing fascia fibroblasts from migrating upwards-led to chronic open wounds. Thus, fascia contains a specialized prefabricated kit of sentry fibroblasts, embedded within a movable sealant, that preassemble together diverse cell types and matrix components needed to heal wounds. Our findings suggest that chronic and excessive skin wounds may be attributed to the mobility of the fascia matrix.

S2k guideline for the treatment of hidradenitis suppurativa / acne inversa - Short version.

The S2k guideline on hidradenitis suppurativa/acne inversa (HS/AI) aims to provide an accepted decision aid for the selection/implementation of appropriate/sufficient therapy. HS/AI is a chronic recurrent, inflammatory, potentially mutilating skin disease of the terminal hair follicle-glandular apparatus, with painful, inflammatory lesions in the apocrine gland-rich regions of the body. Its point prevalence in Germany is 0.3%, it is diagnosed with a delay of 10.0 ± 9.6 years. Abnormal differentiation of the keratinocytes of the hair follicle-gland apparatus and accompanying inflammation form the central pathogenetic basis. Primary HS/AI lesions are inflammatory nodules, abscesses and draining tunnels. Recurrences in the last 6 months with at least 2 lesions at the predilection sites point to HS/AI with a 97% accuracy. HS/AI patients suffer from a significant reduction in quality of life. For correct treatment decisions, classification and activity assessment should be done with a validated tool, such as the International Hidradenitis Suppurativa Severity Scoring System (IHS4). HS/AI is classified into two forms according to the degree of detectable inflammation: active, inflammatory (mild, moderate, and severe according to IHS4) and predominantly inactive, non-inflammatory (Hurley grade I, II and III) HS/AI. Oral tetracyclines or 5-day intravenous therapy with clindamycin are equal to the effectiveness of clindamycin/rifampicin. Subcutaneously administered adalimumab, secukinumab and bimekizumab are approved for the therapy of HS/AI. Various surgical procedures are available for the predominantly non-inflammatory disease form. Drug/surgical combinations are considered a holistic therapy method.

Rydberg exciton-polaritons in a Cu2O microcavity.

Giant Rydberg excitons with principal quantum numbers as high as n = 25 have been observed in cuprous oxide (Cu2O), a semiconductor in which the exciton diameter can become as large as ∼1 µm. The giant dimension of these excitons results in excitonic interaction enhancements of orders of magnitude. Rydberg exciton-polaritons, formed by the strong coupling of Rydberg excitons to cavity photons, are a promising route to exploit these interactions and achieve a scalable, strongly correlated solid-state platform. However, the strong coupling of these excitons to cavity photons has remained elusive. Here, by embedding a thin Cu2O crystal into a Fabry-Pérot microcavity, we achieve strong coupling of light to Cu2O Rydberg excitons up to n = 6 and demonstrate the formation of Cu2O Rydberg exciton-polaritons. These results pave the way towards realizing strongly interacting exciton-polaritons and exploring strongly correlated phases of matter using light on a chip.

Cutaneous innate immune sensing of Toll-like receptor 2-6 ligands suppresses T cell immunity by inducing myeloid-derived suppressor cells.

Skin is constantly exposed to bacteria and antigens, and cutaneous innate immune sensing orchestrates adaptive immune responses. In its absence, skin pathogens can expand, entering deeper tissues and leading to life-threatening infectious diseases. To characterize skin-driven immunity better, we applied living bacteria, defined lipopeptides, and antigens cutaneously. We found suppression of immune responses due to cutaneous infection with Gram-positive S. aureus, which was based on bacterial lipopeptides. Skin exposure to Toll-like receptor (TLR)2-6-binding lipopeptides, but not TLR2-1-binding lipopeptides, potently suppressed immune responses through induction of Gr1(+)CD11b(+) myeloid-derived suppressor cells (MDSCs). Investigating human atopic dermatitis, in which Gram-positive bacteria accumulate, we detected high MDSC amounts in blood and skin. TLR2 activation in skin resident cells triggered interleukin-6 (IL-6), which induced suppressive MDSCs, which are then recruited to the skin suppressing T cell-mediated recall responses such as dermatitis. Thus, cutaneous bacteria can negatively regulate skin-driven immune responses by inducing MDSCs via TLR2-6 activation.

Perioperative antibiotic prophylaxis in skin surgery - Position paper of the Antibiotic Stewardship working group of the German Society for Dermatologic Surgery (DGDC), Part 2: Special indications and situations.

In addition to prevention of surgical site infections after skin surgery, perioperative antibiotic prophylaxis (PAP) aims to prevent the occurrence of other postoperative infectious complications, especially bacterial endocarditis and hematogenous joint prosthesis infections. This article discusses specific indications for the use of PAP. For example, patients who have undergone any type of heart valve replacement, including transcatheter valve replacement or use of prosthetic material to correct the heart valve, or patients who have experienced bacterial endocarditis, require PAP during skin surgery on mucosal membranes or ulcerated tumors. The use of PAP in special situations such as secondary wound healing, septic dermatosurgery or ulcer surgery is also presented and discussed in detail in this paper based on the current scientific literature. This paper represents the second part of the position paper of the Antibiotic Stewardship Working Group of the German Society for Dermatologic Surgery (DGDC) and summarizes evidence-based recommendations for the administration of PAP during skin surgery for special indications and situations. This is particularly important because, as detailed in Part 1 of this position paper, PAP can and usually should be avoided in skin surgery.

Exciton-Exciton Interaction beyond the Hydrogenic Picture in a MoSe_{2} Monolayer in the Strong Light-Matter Coupling Regime.

In transition metal dichalcogenides' layers of atomic-scale thickness, the electron-hole Coulomb interaction potential is strongly influenced by the sharp discontinuity of the dielectric function across the layer plane. This feature results in peculiar nonhydrogenic excitonic states in which exciton-mediated optical nonlinearities are predicted to be enhanced compared to their hydrogenic counterparts. To demonstrate this enhancement, we perform optical transmission spectroscopy of a MoSe_{2} monolayer placed in the strong coupling regime with the mode of an optical microcavity and analyze the results quantitatively with a nonlinear input-output theory. We find an enhancement of both the exciton-exciton interaction and of the excitonic fermionic saturation with respect to realistic values expected in the hydrogenic picture. Such results demonstrate that unconventional excitons in MoSe_{2} are highly favorable for the implementation of large exciton-mediated optical nonlinearities, potentially working up to room temperature.

Emergence of quantum correlations from interacting fibre-cavity polaritons.

Over the past decade, exciton-polaritons in semiconductor microcavities have revealed themselves as one of the richest realizations of a light-based quantum fluid1, subject to fascinating new physics and potential applications2-6. For instance, in the regime of large two-body interactions, polaritons can be used to manipulate the quantum properties of a light field7-9. In this work, we report on the emergence of quantum correlations in laser light transmitted through a fibre-cavity polariton system. We observe a dispersive shape of the autocorrelation function around the polariton resonance that indicates the onset of this regime. The weak amplitude of these correlations indicates a state that still remains far from a low-photon-number state. Nonetheless, given the underlying physical mechanism7, our work opens up the prospect of eventually using polaritons to turn laser light into single photons.

Geometric Pathway to Scalable Quantum Sensing.

Entangled resources enable quantum sensing that achieves Heisenberg scaling, a quadratic improvement on the standard quantum limit, but preparing large N spin entangled states is challenging in the presence of decoherence. We present a quantum control strategy using highly nonlinear geometric phase gates which can be used for generic state or unitary synthesis on the Dicke subspace with O(N) or O(N^{2}) gates, respectively. The method uses a dispersive coupling of the spins to a common bosonic mode and does not require addressability, special detunings, or interactions between the spins. By using amplitude amplification our control sequence for preparing states ideal for metrology can be significantly simplified to O(N^{5/4}) geometric phase gates with action angles O(1/N) that are more robust to mode decay. The geometrically closed path of the control operations ensures the gates are insensitive to the initial state of the mode and the sequence has built-in dynamical decoupling providing resilience to dephasing errors.

Characterization of optofluidic devices for the sorting of sub-micrometer particles.

In this work, we investigate methods of fabricating a device for the optical actuation of nanoparticles. To create the microfluidic channel, we pursued three fabrication methods: SU-8 to molded polydimethylsiloxane soft lithography, laser etching of glass, and deep reactive ion etching of fused silica. We measured the surface roughness of the etched sidewalls, and the laser power transmission through each device. We then measured the radiation pressure on 0.5-µm particles in the best-performing fabricated device (etched fused silica) and in a square glass capillary.

Drug-induced Linear IgA Bullous Dermatosis: A Case Report and Review of the Literature.

Linear IgA bullous dermatosis (LABD) is a rare subepidermal autoimmune blistering disease characterized by linear deposition of IgA along the basement membrane zone. Although most reported cases are idiopathic, there is a subset of patients with drug-induced LABD. Various drugs have been associated with the drug-induced form of the disease. This paper reviews the literature on drugs reported to elicit linear IgA dermatosis and its specific clinical presentation. In addition, a case report of a 77-year-old male patient with linear IgA dermatosis induced by vancomycin is described. The aim of this paper is to emphasize the need to include this differential diagnosis in cases of suspected adverse drug reactions, as well as to highlight the role of drugs in LABD.

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.

IL-4 abrogates T(H)17 cell-mediated inflammation by selective silencing of IL-23 in antigen-presenting cells.

Interleukin 4 (IL-4) can suppress delayed-type hypersensitivity reactions (DTHRs), including organ-specific autoimmune diseases in mice and humans. Despite the broadly documented antiinflammatory effect of IL-4, the underlying mode of action remains incompletely understood, as IL-4 also promotes IL-12 production by dendritic cells (DCs) and IFN-γ-producing T(H)1 cells in vivo. Studying the impact of IL-4 on the polarization of human and mouse DCs, we found that IL-4 exerts opposing effects on the production of either IL-12 or IL-23. While promoting IL-12-producing capacity of DCs, IL-4 completely abrogates IL-23. Bone marrow chimeras proved that IL-4-mediated suppression of DTHRs relies on the signal transducer and activator of transcription 6 (STAT6)-dependent abrogation of IL-23 in antigen-presenting cells. Moreover, IL-4 therapy attenuated DTHRs by STAT6- and activating transcription factor 3 (ATF3)-dependent suppression of the IL-23/T(H)17 responses despite simultaneous enhancement of IL-12/TH1 responses. As IL-4 therapy also improves psoriasis in humans and suppresses IL-23/T(H)17 responses without blocking IL-12/T(H)1, selective IL-4-mediated IL-23/T(H)17 silencing is promising as treatment against harmful inflammation, while sparing the IL-12-dependent T(H)1 responses.

Basic skin care in atopic dermatitis - new and established treatment options.

Basic skin care (basic therapy) is a mainstay in the treatment of atopic dermatitis, irrespective of disease severity and current disease activity. Consistent application of basic skin care plays a key role in restoring skin barrier function and reducing xerosis as well as pruritus. Moreover, it has been shown that concurrent basic therapy has steroid-sparing effects in acute disease flares. In long-term atopic dermatitis management, the use of basic skin care is associated with prolonged recurrence-free intervals. Recent studies have also demonstrated that early initiation of basic skin therapy has protective effects in infants at risk of developing atopic dermatitis. The present review addresses these topics with a focus on established treatments and new developments.

Staphylococcus aureus-derived lipoteichoic acid induces temporary T-cell paralysis independent of Toll-like receptor 2.

BACKGROUND: The interplay between microbes and surface organs, such as the skin, shapes a complex immune system with several checks and balances. The first-line defense is mediated by innate immune pathways leading to inflammation. In the second phase specific T cells invade the infected organ, amplifying inflammation and defense. Consecutively, termination of inflammation is crucial to avoid chronic inflammation triggered by microbes, such as in patients with atopic dermatitis. OBJECTIVE: We aimed to elucidate how the Staphylococcus aureus-derived cell-wall component lipoteichoic acid (LTA) governs the second phase of immune responses when high concentrations of LTA access T cells directly through disrupted skin. METHODS: We analyzed the direct exposure of T cells to LTA in vitro. For in vivo analyses, we used fluorescein isothiocyanate contact hypersensitivity and ovalbumin-induced dermatitis as models for TH2-mediated cutaneous inflammation. RESULTS: We observed that LTA potently suppressed T-lymphocyte activation in a Toll-like receptor 2-independent manner. LTA-exposed T cells did not proliferate and did not produce cytokines. Importantly, these T cells remained completely viable and were responsive to consecutive activation signals on subsequent removal of LTA. Thus LTA exposure resulted in temporary functional T-cell paralysis. In vivo experiments revealed that T-cell cytokine production and cutaneous recall responses were significantly suppressed by LTA. CONCLUSION: We identified a new mechanism through which bacterial compounds directly but temporarily modulate adaptive immune responses.

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.