Homeostatic Control of Sebaceous Glands by Innate Lymphoid Cells Regulates Commensal Bacteria Equilibrium.

Immune cells and epithelium form sophisticated barrier systems in symbiotic relationships with microbiota. Evidence suggests that immune cells can sense microbes through intact barriers, but regulation of microbial commensalism remain largely unexplored. Here, we uncovered spatial compartmentalization of skin-resident innate lymphoid cells (ILCs) and modulation of sebaceous glands by a subset of RORγt+ ILCs residing within hair follicles in close proximity to sebaceous glands. Their persistence in skin required IL-7 and thymic stromal lymphopoietin, and localization was dependent on the chemokine receptor CCR6. ILC subsets expressed TNF receptor ligands, which limited sebocyte growth by repressing Notch signaling pathway. Consequently, loss of ILCs resulted in sebaceous hyperplasia with increased production of antimicrobial lipids and restricted commensalism of Gram-positive bacterial communities. Thus, epithelia-derived signals maintain skin-resident ILCs that regulate microbial commensalism through sebaceous gland-mediated tuning of the barrier surface, highlighting an immune-epithelia circuitry that facilitates host-microbe symbiosis.

Macrophage-mediated extracellular matrix remodeling controls host Staphylococcus aureus susceptibility in the skin.

Hypodermis is the predominant site of Staphylococcus aureus infections that cause cellulitis. Given the importance of macrophages in tissue remodeling, we examined the hypodermal macrophages (HDMs) and their impact on host susceptibility to infection. Bulk and single-cell transcriptomics uncovered HDM subsets with CCR2-dichotomy. HDM homeostasis required the fibroblast-derived growth factor CSF1, ablation of which abrogated HDMs from the hypodermal adventitia. Loss of CCR2- HDMs resulted in accumulation of the extracellular matrix component, hyaluronic acid (HA). HDM-mediated HA clearance required sensing by the HA receptor, LYVE-1. Cell-autonomous IGF1 was required for accessibility of AP-1 transcription factor motifs that controlled LYVE-1 expression. Remarkably, loss of HDMs or IGF1 limited Staphylococcus aureus expansion via HA and conferred protection against cellulitis. Our findings reveal a function for macrophages in the regulation of HA with an impact on infection outcomes, which may be harnessed to limit the establishment of infection in the hypodermal niche.

A hairy situation for ILC2s.

The overall contribution of type 2 immunity to cutaneous barrier integrity is poorly understood. In this issue of Immunity, Ricardo-Gonzalez et al. demonstrate the mechanisms by which type 2 cytokines and group 2 innate lymphoid cells (ILC2s) regulate Demodex mite colonization and maintain skin homeostasis.

Disruption of the endopeptidase ADAM10-Notch signaling axis leads to skin dysbiosis and innate lymphoid cell-mediated hair follicle destruction.

Hair follicles (HFs) function as hubs for stem cells, immune cells, and commensal microbes, which must be tightly regulated during homeostasis and transient inflammation. Here we found that transmembrane endopeptidase ADAM10 expression in upper HFs was crucial for regulating the skin microbiota and protecting HFs and their stem cell niche from inflammatory destruction. Ablation of the ADAM10-Notch signaling axis impaired the innate epithelial barrier and enabled Corynebacterium species to predominate the microbiome. Dysbiosis triggered group 2 innate lymphoid cell-mediated inflammation in an interleukin-7 (IL-7) receptor-, S1P receptor 1-, and CCR6-dependent manner, leading to pyroptotic cell death of HFs and irreversible alopecia. Double-stranded RNA-induced ablation models indicated that the ADAM10-Notch signaling axis bolsters epithelial innate immunity by promoting ß-defensin-6 expression downstream of type I interferon responses. Thus, ADAM10-Notch signaling axis-mediated regulation of host-microbial symbiosis crucially protects HFs from inflammatory destruction, which has implications for strategies to sustain tissue integrity during chronic inflammation.

Choreographing Immunity in the Skin Epithelial Barrier.

The skin interfaces with the external environment and is home to a myriad of immune cells that patrol the barrier to ward off harmful agents and aid in tissue repair. The formation of the cutaneous immune arsenal begins before birth and evolves throughout our lifetime, incorporating exogenous cues from microbes and inflammatory encounters, to achieve optimal fitness and function. Here, we discuss the context-specific signals that drive productive immune responses in the skin epithelium, highlighting key modulators of these reactions, including hair follicles, neurons, and commensal microbes. We thus also discuss the causal and mechanistic underpinning of inflammatory skin diseases that have been revealed in recent years. Finally, we discuss the non-canonical functions of cutaneous immune cells including their burgeoning role in epithelial regeneration and repair. The rapidly growing field of cutaneous immunity is revealing immune mechanisms and functions that can be harnessed to boost skin health and treat disease.

The Neuropeptide CGRP Induces Bipolar Syndrome in Group 2 Innate Lymphoid Cells.

In this issue of Immunity, Nagashima et al., Wallrapp et al., and Xu et al. demonstrate that the neuropeptide calcitonin gene-related peptide (CGRP) fine tunes type 2 innate immune response via suppressing group 2 innate lymphoid cells (ILC2s).

Stress-induced production of chemokines by hair follicles regulates the trafficking of dendritic cells in skin.

Langerhans cells (LCs) are epidermal dendritic cells with incompletely understood origins that associate with hair follicles for unknown reasons. Here we show that in response to external stress, mouse hair follicles recruited Gr-1(hi) monocyte-derived precursors of LCs whose epidermal entry was dependent on the chemokine receptors CCR2 and CCR6, whereas the chemokine receptor CCR8 inhibited the recruitment of LCs. Distinct hair-follicle regions had differences in their expression of ligands for CCR2 and CCR6. The isthmus expressed the chemokine CCL2; the infundibulum expressed the chemokine CCL20; and keratinocytes in the bulge produced the chemokine CCL8, which is the ligand for CCR8. Thus, distinct hair-follicle keratinocyte subpopulations promoted or inhibited repopulation with LCs via differences in chemokine production, a feature also noted in humans. Pre-LCs failed to enter hairless skin in mice or humans, which establishes hair follicles as portals for LCs.

Dysbiosis and Staphylococcus aureus Colonization Drives Inflammation in Atopic Dermatitis.

Staphylococcus aureus skin colonization is universal in atopic dermatitis and common in cancer patients treated with epidermal growth factor receptor inhibitors. However, the causal relationship of dysbiosis and eczema has yet to be clarified. Herein, we demonstrate that Adam17(fl/fl)Sox9-(Cre) mice, generated to model ADAM17-deficiency in human, developed eczematous dermatitis with naturally occurring dysbiosis, similar to that observed in atopic dermatitis. Corynebacterium mastitidis, S. aureus, and Corynebacterium bovis sequentially emerged during the onset of eczematous dermatitis, and antibiotics specific for these bacterial species almost completely reversed dysbiosis and eliminated skin inflammation. Whereas S. aureus prominently drove eczema formation, C. bovis induced robust T helper 2 cell responses. Langerhans cells were required for eliciting immune responses against S. aureus inoculation. These results characterize differential contributions of dysbiotic flora during eczema formation, and highlight the microbiota-host immunity axis as a possible target for future therapeutics in eczematous dermatitis.

Nanoprocessing of Self-Suspended Monolayer Graphene and Defect Formation by Femtosecond-Laser Irradiation.

We demonstrate the femtosecond-laser processing of self-suspended monolayer graphene grown by chemical vapor deposition, resulting in multipoint drilling with holes having a diameter of <100 nm. Scanning transmission electron microscopy revealed the formation of many nanopores on the laser-irradiated graphene. Furthermore, atomic-level defects as well as nanopores were found in the graphene membrane by high-resolution transmission electron microscopy, while the overall crystal structure remained intact. Raman spectroscopy showed an increase in the defect density with an increase in the number of laser shots, suggesting that the nanopore formation triggered the creation of the <100 nm holes. The approach presented herein can offer an experimental insight into the simulation of atomic dynamics in graphene under femtosecond-laser irradiation. The thorough examination of the atomic defect formation and secondary effect of surface cleaning observed in this study would help develop engineering methods for graphene and other two-dimensional materials in the future.

Skin-Resident Innate Lymphoid Cells - Cutaneous Innate Guardians and Regulators.

Skin is the largest barrier organ and an important interface between the body and the outside environment. Immune surveillance and homeostatic regulation of skin function are governed by complex interactions between resident lymphoid and myeloid cells and their communications with the surrounding parenchyma. Recent studies have provided exciting insights about the unique characteristics of skin-resident innate lymphoid cells (ILCs). Here, we discuss advances demonstrating how skin ILCs contribute to tissue homeostasis by regulating microbiome balance in steady-state and how their dysregulation can trigger and promote inflammatory skin diseases such as atopic dermatitis and psoriasis. We review the phenotypic and functional similarities and differences of ILCs between the skin and other organs and highlight future areas of investigation for this field.

The DNA integrity number and concentration are useful parameters for successful comprehensive genomic profiling test for cancer using formalin-fixed paraffin embedded tissue.

The acquisition of high-quality biospecimens and the appropriate handling of these materials are indispensable for successful clinical sequencing. We developed a cancer clinical sequencing system targeting 160 cancer genes: PleSSision-Rapid. Through the PleSSision-Rapid system, we have analyzed DNA quality evaluated by DIN (DNA integrity number) with 1329 formalin-fixed paraffin embedded (FFPE) samples including 477 prospectively collected tissues for genomic test (P) and 852 archival samples after routine pathological diagnosis (A1/A2). As a result, the samples with more than DIN 2.1 was 92.0% (439/477) in prospectively collected sample (P), while it was 85.6% (332/388) and 76.7% (356/464) in two types of archival samples (A1/A2). We performed the PleSSision-Rapid sequence using the samples with over DIN 2.1 and DNA concentration >10 ng/µL with which we were able to construct a DNA library, and the probability of sequence success was almost equivalent during all types of specimen processing, at 90.7% (398/439) in (P), 92.5% (307/332) in (A1) and 90.2% (321/356) in (A2), respectively. Our result indicated the clinical benefit to prepare the prospective collection of FFPE materials for indisputable clinical sequence, and that DIN ≥ 2.1 would be a solid parameter for sample preparation of comprehensive genomic profiling tests.

The discovery of group 2 innate lymphoid cells has changed the concept of type 2 immune diseases.

Group 2 innate lymphoid cells (ILC2s), discovered in 2010, have been recognized as immune cells with unique functions and their involvement in various diseases has been clarified. Before 2010, the antigen-specific response was a primary focus of immunology research, and immune responses were considered almost equivalent to biological responses to foreign antigens. However, with the emergence of ILC2s, the importance of 'antigen-independent responses' was confirmed, and this concept has permeated basic and clinical research as well as drug development. When ILC2s were discovered, their function in the acute phase of diseases garnered attention because of their rapid and potent type 2 immune response. However, several studies have revealed that the main role of ILC2s is more closely related to the chronicity of diseases, such as allergy and fibrosis, than to the induction of diseases. In this review, we discuss how ILC2 research has affected the concept of 'Taishitsu', a Japanese term describing the overall nature of an individual as determined by the interaction of genetic and acquired predisposition.

Transmission Network of Measles During the Yamagata Outbreak in Japan, 2017.

BACKGROUND: A measles outbreak involving 60 cases occurred in Yamagata, Japan in 2017. Using two different mathematical models for different datasets, we aimed to estimate measles transmissibility over time and explore any heterogeneous transmission patterns. METHODS: The first model relied on the temporal distribution for date of illness onset for cases, and a generation-dependent model was applied to the data. Another model focused on the transmission network. Using the illness-onset date along with the serial interval and geographical location of exposure, we reconstructed a transmission network with 19 unknown links. We then compared the number of secondary transmissions with and without clinical symptoms or laboratory findings. RESULTS: Using a generation-dependent model (assuming three generations other than the index case), the reproduction number (R) over generations 0, 1, and 2 were 25.3, 1.3, and <0.1, respectively, explicitly yielding the transmissibility over each generation. The network data enabled us to demonstrate that both the mean and the variance for the number of secondary transmissions per primary case declined over time. Comparing primary cases with and without secondary transmission, high viral shedding was the only significant determinant (P < 0.01). CONCLUSIONS: The R declined abruptly over subsequent generations. Use of network data revealed the distribution of the number of secondary transmissions per primary case and also allowed us to identify possible secondary transmission risk factors. High viral shedding from the throat mucosa was identified as a potential predictor of secondary transmission.

Efficacy of a new enzyme-linked immunosorbent assay system for three islet cell autoantibodies in Japanese patients with acute-onset type 1 diabetes.

To evaluate the clinical efficacy of a new enzyme-linked immunosorbent assay (ELISA) system for simultaneously detecting three islet cell autoantibodies against glutamic acid decarboxylase (GADA), insulinoma-associated antigen-2 (IA-2A), and zinc transporter 8 (ZnT8A) (3 Screen ICA ELISA) in Japanese patients with acute-onset type 1 diabetes (T1D). In addition, clinical factors affecting the 3 Screen ICA ELISA index were investigated. We compared the positivity values of 3 Screen ICA ELISA with that of each autoantibody alone in 97 patients with acute-onset T1D (mean age 48.7 years, 49% male) and 100 non-diabetic subjects (mean age 47.0 years, 50% male). Serum thyroid stimulating hormone receptor antibody, thyroid peroxidase antibody (TPOAb) and thyroglobulin autoantibody levels were also evaluated. The cut-off value of the 3 Screen ICA ELISA was determined based on the 97th percentile of 100 non-diabetic controls (threshold for positivity, ≥14 index). The mean age of disease onset and duration of diabetes were 34.2 years and 14.5 years, respectively. Among all T1D patients, the positivity of 3 Screen ICA ELISA was 71.1%, while that of GADA, IA-2A, and ZnT8A were 59.8%, 25.8%, and 25.8%, respectively. The median 3 Screen ICA index was 121.9 (8.7-468.2) and was associated with titers of each autoantibody, most so with GADA, and was significantly higher in TPOAb-positive patients than in TPOAb-negative patients. Our findings suggests that the 3 Screen ICA ELISA may be a time-saving diagnostic tool for evaluating islet autoantibodies in acute-onset T1D patients.

ILCs and Allergy.

The recent discovery of new innate lymphoid cells (ILCs) has revolutionized the field of allergies. Since most allergic diseases induce a type 2 immune response, Th2 cells, which produce IL-4, IL-5, and IL-13 in an antigen-dependent manner, in addition to basophils and mast cells which are activated by antigen-specific IgE, are thought to play a major role in the pathogenesis. However, since group 2 innate lymphoid cells (ILC2s) produce type 2 cytokines (i.e., IL-2, IL-4, IL-5, IL-6, IL-9, IL-13, GM-CSF, and amphiregulin) in response to various cytokines, including IL-33 in the surrounding environment, the possibility has emerged that there are two types of allergies: allergies induced in an antigen-dependent manner by Th2 cells and allergies induced in an antigen-independent manner by ILC2s. In order to make an impact on the increasing incidence of allergic diseases in the world, it is essential to research and develop new treatments that focus not only on Th2 cells but also on ILC2s. In this chapter, the role of ILCs in allergic diseases, which has rapidly changed with the discovery of ILCs, is discussed, focusing mainly on ILC2s.

Cell-autonomous FLT3L shedding via ADAM10 mediates conventional dendritic cell development in mouse spleen.

Conventional dendritic cells (cDCs) derive from bone marrow (BM) precursors that undergo cascades of developmental programs to terminally differentiate in peripheral tissues. Pre-cDC1s and pre-cDC2s commit in the BM to each differentiate into CD8α+/CD103+ cDC1s and CD11b+ cDC2s, respectively. Although both cDCs rely on the cytokine FLT3L during development, mechanisms that ensure cDC accessibility to FLT3L have yet to be elucidated. Here, we generated mice that lacked a disintegrin and metalloproteinase (ADAM) 10 in DCs (Itgax-cre × Adam10-fl/fl; ADAM10∆DC) and found that ADAM10 deletion markedly impacted splenic cDC2 development. Pre-cDC2s accumulated in the spleen with transcriptomic alterations that reflected their inability to differentiate and exhibited abrupt failure to survive as terminally differentiated cDC2s. Induced ADAM10 ablation also led to the reduction of terminally differentiated cDC2s, and restoration of Notch signaling, a major pathway downstream of ADAM10, only modestly rescued them. ADAM10∆DC BM failed to generate cDC2s in BM chimeric mice with or without cotransferred ADAM10-sufficient BM, indicating that cDC2 development required cell-autonomous ADAM10. We determined cDC2s to be sources of soluble FLT3L, as supported by decreased serum FLT3L concentration and the retention of membrane-bound FLT3L on cDC2 surfaces in ADAM10∆DC mice, and by demonstrating the release of soluble FLT3L by cDC2 in ex vivo culture supernatants. Through in vitro studies utilizing murine embryonic fibroblasts, we determined FLT3L to be a substrate for ADAM10. These data collectively reveal cDC2s as FLT3L sources and highlight a cell-autonomous mechanism that may enhance FLT3L accessibility for cDC2 development and survival.

Theoretical and Experimental Studies of KLi6TaO6 as a Li-Ion Solid Electrolyte.

We study a hexagonal oxide KLi6TaO6 (KLTO), proposed as a Li-ion solid electrolyte, by using a recently developed screening method. First-principles calculations predict that KLTO presents a good Li-ion conductivity (σLi) and a low activation energy (Ea). Li migration is enhanced by the presence of excess Li ions in the interstitial region via a kick-out mechanism. Our experimental results demonstrate that Sn-doped KLTO presents a conductivity of 1 × 10-5 S cm-1, a σLi of 6 × 10-6 S cm-1, and a relatively low Ea of 36 kJ mol-1, which confirm the validity of the proposed screening method. Conversely, detailed analyses of the microstructure and X-ray diffraction patterns of KLTO samples indicate that a stable Li-excess condition is not achieved, therefore leaving potential improvement of the performance of KLTO as a Li-ion solid electrolyte by optimizing extrinsic doping and fabrication processes.

Epithelial-immune crosstalk with the skin microbiota in homeostasis and atopic dermatitis - a mini review.

The skin is a complex and dynamic ecosystem, wherein epithelial cells, immune cells and the skin microbiota actively interact and maintain barrier integrity and functional immunity. Skin microbes actively tune the functions of the resident immune cells. Dysbiosis - alterations in the resident microbiota - leads to the dysregulation of host immunity. Microbiome analyses in humans and dogs with atopic dermatitis (AD) have shown shifts in microbial diversity, and in particular, an increased proportion of staphylococci. Monogenic diseases that manifest AD-like symptoms provide insights into the pathogenesis of AD and the mechanisms of dysbiosis, from both the epithelial and immunological perspectives. The symbiotic relationships between the host and microbiota must be maintained constitutively. Detailed mechanisms of how host immunity regulates commensal bacteria in the steady state have been reported. The skin harbours multiple tissue-resident immune cells, including both innate and adaptive immune cells. Recent studies have highlighted the fundamental role of innate lymphoid cells (ILCs) in the maintenance of barrier functions and tissue homeostasis. ILCs directly respond to tissue-derived signals and are instrumental in barrier immunity. Epithelial cells produce alarmins such as thymic stromal lymphopoietin (TSLP) and interleukins (IL)-33 and IL-25, all of which activate group 2 ILCs (ILC2s), which produce type 2 cytokines, such as IL-5 and IL-13, boosting type 2 immune reactions. Dysregulation of the epithelial-ILC crosstalk results in allergic inflammation. This review highlights our understanding of the active interactions between the host epithelial and immune cells, and microbiota, providing a foundation for novel therapeutic strategies for inflammatory skin diseases.

La peau est un écosystème complexe et dynamique, tandis que les cellules épithéliales, les cellules immunitaires et le microbiote cutané interagissent activement et maintiennent l'intégrité de la barrière et de l'immunité. Les microbes cutanés règlent activement les fonctions des cellules immunitaires résidentes. La dysbiose - altérations du microbiote résident - mène à la dérégulation de l'immunité de l'hôte. Les analyses du microbiome chez l'homme et le chien avec dermatite atopique (AD) ont montré les shifts de diversité microbienne, et en particulier, une augmentation de la proportion de staphylocoques. Les maladies monogéniques qui manifestent des symptômes AD-like fournissent des données sur la pathogénie de AD et des mécanismes de dysbiose, à la fois de perspectives épithéliales et immunologiques. Les relations symbiotiques entre l'hôte et le microbiote doit être maintenu constitutivement. Les mécanismes détaillés de comment l'immunité de l'hôte régule les bactéries commensales dans l'état ont été décrits. La peau possède différentes cellules immunitaires résidents comprenant à la fois des cellules des systèmes immunitaires inné et adaptatif. Des études récente ont montré le rôle fondamental des cellules lymphoïdes innées (ILCs) dans le maintien des fonctions barrières et homéostasie tissulaire. Les ILCs répondent directement aux signaux dérivés des tissus et sont instrumentaux dans l'immunité de barrière. Les cellules épithéliales produisent des alamines tels que TSLP (thymic stromal lymphopoietin) et interleukines (IL)-33 et IL-25, toutes activant les ILCs du groupe 2 (ILC2s), produisent des cytokines de type 2 telles que IL-5 et IL-13, boostant l'immunité de type 2. La dérégulation des résultats de epithelial-ILC résulte en une inflammation allergique. Cette revue insiste sur nos connaissances sur les interactions actives entre les cellules immunitaires et épithéliales de l'hôte et le microbiote, fournissant une base pour de nouvelles stratégies thérapeutiques pour les maladies cutanés inflammatoires.

La piel es un ecosistema complejo y dinámico, en el que las células epiteliales, las células inmunitarias y la microbiota cutánea interactúan activamente y mantienen la integridad de la barrera y la inmunidad funcional. Los microbios de la piel sintonizan activamente las funciones de las células inmunitarias residentes. La disbiosis (alteraciones en la microbiota residente) conduce a la disregulación de la inmunidad del huésped. Los análisis de microbiomas en humanos y perros con dermatitis atópica (AD) han mostrado cambios en la diversidad microbiana y, en particular, una mayor proporción de estafilococos. Las enfermedades monogénicas que manifiestan síntomas similares a la AD proporcionan información sobre la patogénesis de la AD y los mecanismos de la disbiosis, tanto desde la perspectiva epitelial como inmunológica. Las relaciones simbióticas entre el huésped y la microbiota deben mantenerse de manera constitutiva. Mecanismos detallados de cómo la inmunidad del huésped regula las bacterias comensales en el estado normal han sido descritos. La piel alberga múltiples células inmunitarias residentes en los tejidos, incluidas células inmunitarias tanto innatas como adaptativas. Estudios recientes han destacado el papel fundamental de las células linfoides innatas (ILCs) en el mantenimiento de las funciones de barrera y la homeostasis tisular. Las ILCs responden directamente a señales derivadas de tejidos y son fundamentales en la inmunidad de barrera. Las células epiteliales producen alarminas como la linfopoyetina del estroma tímico (TSLP) y las interleuquinas (IL) -33 e IL-25, todas las cuales activan las ILCs del grupo 2 (ILC2s), que producen citocqunas de tipo 2, como IL-5 e IL-13, estimulando las reacciones inmunes de tipo 2. La disregulación de la interacción epitelio-ILCs da como resultado una inflamación alérgica. Esta revisión destaca nuestra comprensión de las interacciones activas entre las células epiteliales e inmunes del huésped y la microbiota, proporcionando una base para nuevas estrategias terapéuticas en enfermedades inflamatorias de la piel.

A pele é um ecossistema complexo e dinâmico, em que as células epiteliais, as células imunológicas e a microbiota cutânea interagem ativamente e mantêm a integridade da barreira e a imunidade funcional. Os microrganismos da pele ajustam ativamente as funções das células imunes residentes. Disbiose - alterações na microbiota residente - leva à desregulação da imunidade do hospedeiro. As análises de microbioma em humanos e cães com dermatite atópica (DA) demonstraram mudanças na diversidade microbiana e, em particular, um aumento na proporção de estafilococos. Doenças monogênicas que manifestam sintomas semelhantes aos da DA fornecem informações sobre a patogênese da DA e os mecanismos da disbiose, tanto sob o ponto de vista epitelial quanto imunológico. As relações simbióticas entre o hospedeiro e a microbiota devem ser mantidas constitutivamente. Mecanismos detalhados de como a imunidade do hospedeiro regula as bactérias comensais no estado estacionário foram relatados. A pele abriga várias células imunes residentes no tecido, incluindo células imunes inatas e adaptativas. Estudos recentes têm destacado o papel fundamental das células linfoides inatas (ILCs) na manutenção das funções de barreira e homeostase tecidual. Os ILCs respondem diretamente aos sinais derivados de tecidos e são fundamentais para a imunidade de barreira. As células epiteliais produzem alarminas, como linfopoietina estromal tímica (TSLP) e interleucinas (IL) -33 e IL-25, todas ativando ILCs do grupo 2 (ILC2s), que produzem citocinas tipo 2, como IL-5 e IL-13, estimulando as reações imunológicas do tipo 2. A desregulação da comunicação epitelial-ILC resulta em inflamação alérgica. Esta revisão destaca nossa compreensão das interações ativas entre as células epiteliais e imunológicas do hospedeiro e microbiota, fornecendo uma base para novas estratégias terapêuticas para doenças inflamatórias da pele.

Host-microbial dialogues in atopic dermatitis.

Recent advances in sequencing technologies have revealed the diversity of microbes that reside on the skin surface which has enhanced our understanding on skin as an ecosystem, wherein the epidermis, immune cells and the microbiota engage in active dialogues that maintain barrier integrity and functional immunity. This mutual dialogue is altered in atopic dermatitis (AD), in which an impaired epidermal barrier, the skin microbial flora and aberrant immunity can form a vicious cycle that leads to clinical manifestations as eczematous dermatitis. Microbiome studies have revealed an altered microbial landscape in AD and genetic studies have identified genes that underlie barrier impairment and immune dysregulation. Shifting from the long-standing notion that AD was mediated by conventional allergic responses, emerging data suggest that it is a disorder of an altered host-microbial relationship with sophisticated pathophysiology. In this review, we will discuss recent advancements that suggest the roles of the skin microbiota in AD pathophysiology, genetic factors that mediate barrier impairment, dysbiosis and inflammation. Studies in mice, classic AD and monogenic disorders that manifest as AD collectively facilitate our understanding of AD pathophysiology and provide a foundation for novel therapeutic strategies.

Crucial role of Reg I from acinar-like cell cluster touching with islets (ATLANTIS) on mitogenesis of beta cells in EMC virus-induced diabetic mice.

Recently, we reported the presence of distinct cell clusters named acinar-like cell clusters touching Langerhans islets with thin interstitial surrounding (ATLANTIS) in human pancreas. A morphological study in humans demonstrated that ATLANTIS and islet cell clusters are found together in the microenvironment enclosed by a common basement membrane, and ATLANTIS releases vesicles containing Regenerating gene protein (REG Iα) to islet cell clusters. We examined 1) the presence or absence of ATLANTIS in homozygous Reg I (mouse homologue of human REG Iα) deficient (Reg I-/-) and wild-type mice, and 2) the possible role of ATLANTIS in the regeneration of beta cell clusters after encephalomyocarditis (EMC) virus (D-variant) infection in Reg I-/- and wild-type mice. ATLANTIS was found in both wild-type and Reg I-/- mice. In both groups, mean blood glucose increased transiently to greater than 14.0 mmol/L at 5 days after EMC virus infection and recovered to baseline at 12 days. At 12 days after EMC virus infection, lower BrdU labeling indices were observed in islet beta cells of Reg I-/- mice compared to wild-type mice. Beta cell volume 12 days after EMC virus infection in Reg I-/- mice did not differ from that of wild-type mice. These results suggest that Reg I, which is released from ATLANTIS to islet beta cell clusters, has a crucial role in beta cell regeneration in EMC virus-induced diabetes. The presence of mechanism(s) other than that mediated by Reg I in beta cell restoration after destruction by EMC virus was also suggested.