S. aureus drives itch and scratch-induced skin damage through a V8 protease-PAR1 axis.

Itch is an unpleasant sensation that evokes a desire to scratch. The skin barrier is constantly exposed to microbes and their products. However, the role of microbes in itch generation is unknown. Here, we show that Staphylococcus aureus, a bacterial pathogen associated with itchy skin diseases, directly activates pruriceptor sensory neurons to drive itch. Epicutaneous S. aureus exposure causes robust itch and scratch-induced damage. By testing multiple isogenic bacterial mutants for virulence factors, we identify the S. aureus serine protease V8 as a critical mediator in evoking spontaneous itch and alloknesis. V8 cleaves proteinase-activated receptor 1 (PAR1) on mouse and human sensory neurons. Targeting PAR1 through genetic deficiency, small interfering RNA (siRNA) knockdown, or pharmacological blockade decreases itch and skin damage caused by V8 and S. aureus exposure. Thus, we identify a mechanism of action for a pruritogenic bacterial factor and demonstrate the potential of inhibiting V8-PAR1 signaling to treat itch.

Author Correction: A regulatory T cell Notch4-GDF15 axis licenses tissue inflammation in asthma.

A Correction to this paper has been published: https://doi.org/10.1038/s41590-021-00929-x.

A regulatory T cell Notch4-GDF15 axis licenses tissue inflammation in asthma.

Elucidating the mechanisms that sustain asthmatic inflammation is critical for precision therapies. We found that interleukin-6- and STAT3 transcription factor-dependent upregulation of Notch4 receptor on lung tissue regulatory T (Treg) cells is necessary for allergens and particulate matter pollutants to promote airway inflammation. Notch4 subverted Treg cells into the type 2 and type 17 helper (TH2 and TH17) effector T cells by Wnt and Hippo pathway-dependent mechanisms. Wnt activation induced growth and differentiation factor 15 expression in Treg cells, which activated group 2 innate lymphoid cells to provide a feed-forward mechanism for aggravated inflammation. Notch4, Wnt and Hippo were upregulated in circulating Treg cells of individuals with asthma as a function of disease severity, in association with reduced Treg cell-mediated suppression. Our studies thus identify Notch4-mediated immune tolerance subversion as a fundamental mechanism that licenses tissue inflammation in asthma.

Mechanical Skin Injury Promotes Food Anaphylaxis by Driving Intestinal Mast Cell Expansion.

Mast cell (MC) mediator release after crosslinking of surface-bound IgE antibody by ingested antigen underlies food allergy. However, IgE antibodies are not uniformly associated with food allergy, and intestinal MC load is an important determinant. Atopic dermatitis (AD), characterized by pruritis and cutaneous sensitization to allergens, including foods, is strongly associated with food allergy. Tape stripping mouse skin, a surrogate for scratching, caused expansion and activation of small intestinal MCs, increased intestinal permeability, and promoted food anaphylaxis in sensitized mice. Tape stripping caused keratinocytes to systemically release interleukin-33 (IL-33), which synergized with intestinal tuft-cell-derived IL-25 to drive the expansion and activation of intestinal type-2 innate lymphoid cells (ILC2s). These provided IL-4, which targeted MCs to expand in the intestine. Duodenal MCs were expanded in AD. In addition to promoting cutaneous sensitization to foods, scratching may promote food anaphylaxis in AD by expanding and activating intestinal MCs.

Basophils are important for development of allergic skin inflammation.

BACKGROUND: Atopic dermatitis skin lesions exhibit increased infiltration by basophils. Basophils produce IL-4, which plays an important role in the pathogenesis of atopic dermatitis. OBJECTIVE: We sought to determine the role of basophils in a mouse model of antigen-driven allergic skin inflammation. METHODS: Wild-type mice, mice with selective and inducible depletion of basophils, and mice expressing Il4-driven enhanced green fluorescent protein were subjected to epicutaneous sensitization with ovalbumin or saline. Sensitized skin was examined by histology for epidermal thickening. Cells were analyzed for surface markers and intracellular expression of enhanced green fluorescent protein by flow cytometry. Gene expression was evaluated by real-time reverse transcription-quantitative PCR. RESULTS: Basophils were important for epidermal hyperplasia, dermal infiltration by CD4+ T cells, mast cells, and eosinophils in ovalbumin-sensitized mouse skin and for the local and systemic TH2 response to epicutaneous sensitization. Moreover, basophils were the major source of IL-4 in epicutaneous-sensitized mouse skin and promote the ability of dendritic cells to drive TH2 polarization of naive T cells. CONCLUSION: Basophils play an important role in the development of allergic skin inflammation induced by cutaneous exposure to antigen in mice.

IL-4 acts on skin-derived dendritic cells to promote the TH2 response to cutaneous sensitization and the development of allergic skin inflammation.

BACKGROUND: Atopic dermatitis is characterized by scratching and a TH2-dominated local and systemic response to cutaneously encountered antigens. Dendritic cells (DCs) capture antigens in the skin and rapidly migrate to draining lymph nodes (dLNs) where they drive the differentiation of antigen-specific naive T cells. OBJECTIVE: We sought to determine whether non-T-cell-derived IL-4 acts on skin-derived DCs to promote the TH2 response to cutaneously encountered antigen and allergic skin inflammation. METHODS: DCs from dLNs of ovalbumin (OVA)-exposed skin were analyzed by flow cytometry and for their ability to polarize OVA-specific naive CD4+ T cells. Skin inflammation following epicutaneous sensitization of tape-stripped skin was assessed by flow cytometry of skin cells and real-time quantitative PCR of cytokines. Cytokine secretion and antibody levels were evaluated by ELISA. RESULTS: Scratching upregulated IL4 expression in human skin. Similarly, tape stripping caused rapid basophil-dependent upregulation of cutaneous Il4 expression in mouse skin. In vitro treatment of DCs from skin dLNs with IL-4 promoted their capacity to drive TH2 differentiation. DCs from dLNs of OVA-sensitized skin of Il4-/- mice and CD11c-CreIl4rflox/- mice, which lack IL-4Rα expression in DCs (DCΔ/Δll4ra mice), were impaired in their capacity to drive TH2 polarization compared with DCs from controls. Importantly, OVA-sensitized DCΔ/Δll4ra mice demonstrated impaired allergic skin inflammation and OVA-specific systemic TH2 response evidenced by reduced TH2 cytokine secretion by OVA-stimulated splenocytes and lower levels of OVA-specific IgE and IgG1 antibodies, compared with controls. CONCLUSIONS: Mechanical skin injury causes basophil-dependent upregulation of cutaneous IL-4. IL-4 acts on skin DCs that capture antigen and migrate to dLNs to promote their capacity for TH2 polarization and drive allergic skin inflammation.

Regulatory T-cell dysfunction and cutaneous exposure to Staphylococcus aureus underlie eczema in DOCK8 deficiency.

BACKGROUND: Dedicator of cytokinesis 8 (DOCK8)-deficient patients have severe eczema, elevated IgE, and eosinophilia, features of atopic dermatitis (AD). OBJECTIVE: We sought to understand the mechanisms of eczema in DOCK8 deficiency. METHODS: Skin biopsy samples were characterized by histology, immunofluorescence microscopy, and gene expression. Skin barrier function was measured by transepidermal water loss. Allergic skin inflammation was elicited in mice by epicutaneous sensitization with ovalbumin (OVA) or cutaneous application of Staphylococcus aureus. RESULTS: Skin lesions of DOCK8-deficient patients exhibited type 2 inflammation, and the patients' skin was colonized by Saureus, as in AD. Unlike in AD, DOCK8-deficient patients had a reduced FOXP3:CD4 ratio in their skin lesions, and their skin barrier function was intrinsically intact. Dock8-/- mice exhibited reduced numbers of cutaneous T regulatory (Treg) cells and a normal skin barrier. Dock8-/- and mice with an inducible Dock8 deletion in Treg cells exhibited increased allergic skin inflammation after epicutaneous sensitization with OVA. DOCK8 was shown to be important for Treg cell stability at sites of allergic inflammation and for the generation, survival, and suppressive activity of inducible Treg cells. Adoptive transfer of wild-type, but not DOCK8-deficient, OVA-specific, inducible Treg cells suppressed allergic inflammation in OVA-sensitized skin of Dock8-/- mice. These mice developed severe allergic skin inflammation and elevated serum IgE levels after topical exposure to Saureus. Both were attenuated after adoptive transfer of WT but not DOCK8-deficient Treg cells. CONCLUSION: Treg cell dysfunction increases susceptibility to allergic skin inflammation in DOCK8 deficiency and synergizes with cutaneous exposure to Saureus to drive eczema in DOCK8 deficiency.

IL-4 receptor alpha blockade dampens allergic inflammation and upregulates IL-17A expression to promote Saureus clearance in antigen sensitized mouse skin.

BACKGROUND: Skin colonization with Staphylococcus aureus aggravates atopic dermatitis and exaggerates allergic skin inflammation in mice. IL-4 receptor α (IL-4Rα) blockade is beneficial in atopic dermatitis and reduces Saureus skin colonization through unknown mechanisms. The cytokine IL-17A restrains Saureus growth. OBJECTIVES: This study sought to examine the effect of IL-4Rα blockade on Saureus colonization at sites of allergic skin inflammation in mice and determine the mechanism involved. METHODS: BALB/c mice were epicutaneously sensitized with ovalbumin (OVA). Immediately after, PSVue 794-labeled S aureus strain SF8300 or saline was applied and a single dose of anti-IL-4Rα blocking antibody, a mixture of anti-IL-4Rα and anti-IL-17A blocking antibodies, or IgG isotype controls were administered intradermally. Saureus load was assessed 2 days later by in vivo imaging and enumeration of colony forming units. Skin cellular infiltration was examined by flow cytometry and gene expression by quantitative PCR and transcriptome analysis. RESULTS: IL-4Rα blockade decreased allergic skin inflammation in OVA-sensitized skin, as well as in OVA-sensitized and Saureus-exposed skin, evidenced by significantly decreased epidermal thickening and reduced dermal infiltration by eosinophils and mast cells. This was accompanied by increased cutaneous expression of Il17a and IL-17A-driven antimicrobial genes with no change in Il4 and Il13 expression. IL-4Rα blockade significantly decreased Saureus load in OVA-sensitized and S aureus-exposed skin. IL-17A blockade reversed the beneficial effect of IL-4Rα blockade on Saureus clearance and reduced the cutaneous expression of IL-17A-driven antimicrobial genes. CONCLUSIONS: IL-4Rα blockade promotes Saureus clearance from sites of allergic skin inflammation in part by enhancing IL-17A expression.

The IL-4Rα Q576R polymorphism is associated with increased severity of atopic dermatitis and exaggerates allergic skin inflammation in mice.

BACKGROUND: Atopic dermatitis (AD) is characterized by TH2-dominated skin inflammation and systemic response to cutaneously encountered antigens. The TH2 cytokines IL-4 and IL-13 play a critical role in the pathogenesis of AD. The Q576->R576 polymorphism in the IL-4 receptor alpha (IL-4Rα) chain common to IL-4 and IL-13 receptors alters IL-4 signaling and is associated with asthma severity. OBJECTIVE: We sought to investigate whether the IL-4Rα R576 polymorphism is associated with AD severity and exaggerates allergic skin inflammation in mice. METHODS: Nighttime itching interfering with sleep, Rajka-Langeland, and Eczema Area and Severity Index scores were used to assess AD severity. Allergic skin inflammation following epicutaneous sensitization of mice 1 or 2 IL-4Rα R576 alleles (QR and RR) and IL-4Rα Q576 (QQ) controls was assessed by flow cytometric analysis of cells and quantitative RT-PCR analysis of cytokines in skin. RESULTS: The frequency of nighttime itching in 190 asthmatic inner-city children with AD, as well as Rajka-Langeland and Eczema Area and Severity Index scores in 1116 White patients with AD enrolled in the Atopic Dermatitis Research Network, was higher in subjects with the IL-4Rα R576 polymorphism compared with those without, with statistical significance for the Rajka-Langeland score. Following epicutaneous sensitization of mice with ovalbumin or house dust mite, skin infiltration by CD4+ cells and eosinophils, cutaneous expression of Il4 and Il13, transepidermal water loss, antigen-specific IgE antibody levels, and IL-13 secretion by antigen-stimulated splenocytes were significantly higher in RR and QR mice compared with QQ controls. Bone marrow radiation chimeras demonstrated that both hematopoietic cells and stromal cells contribute to the mutants' exaggerated allergic skin inflammation. CONCLUSIONS: The IL-4Rα R576 polymorphism predisposes to more severe AD and increases allergic skin inflammation in mice.

The Dengue Virus Nonstructural Protein 1 (NS1) Interacts with the Putative Epigenetic Regulator DIDO1 to Promote Flavivirus Replication in Mosquito Cells.

Dengue virus (DENV) NS1 is a multifunctional protein essential for viral replication. To gain insights into NS1 functions in mosquito cells, the protein interactome of DENV NS1 in C6/36 cells was investigated using a proximity biotinylation system and mass spectrometry. A total of 817 mosquito targets were identified as protein-protein interacting with DENV NS1. Approximately 14% of them coincide with interactomes previously obtained in vertebrate cells, including the oligosaccharide transferase complex, the chaperonin containing TCP-1, vesicle localization, and ribosomal proteins. Notably, other protein pathways not previously reported in vertebrate cells, such as epigenetic regulation and RNA silencing, were also found in the NS1 interactome in mosquito cells. Due to the novel and strong interactions observed for NS1 and the epigenetic regulator DIDO1 (Death-Inducer Obliterator 1), the role of DIDO1 in viral replication was further explored. Interactions between NS1 and DIDO1 were corroborated in infected mosquito cells, by colocalization and proximity ligation assays. Silencing DIDO1 expression results in a significant reduction in DENV and ZIKV replication and progeny production. Comparison of transcription analysis of mock or DENV infected cells silenced for DIDO1 revealed variations in multiple gene expression pathways, including pathways associated with DENV infection such as RNA surveillance, IMD, and Toll. These results suggest that DIDO1 is a host factor involved in the negative modulation of the antiviral response necessary for flavivirus replication in mosquito cells. Our findings uncover novel mechanisms of NS1 to promote DENV and ZIKV replication, and add to the understanding of NS1 as a multifunctional protein. IMPORTANCE Dengue is the most important mosquito-borne viral disease to humans. Dengue virus NS1 is a multifunctional protein essential for replication and modulation of innate immunity. To gain insights into NS1 functions, the protein interactome of dengue virus NS1 in Aedes albopictus cells was investigated using a proximity biotinylation system and mass spectrometry. Several protein pathways, not previously observed in vertebrate cells, such as transcription and epigenetic regulation, were found as part of the NS1 interactome in mosquito cells. Among those, DIDO1 was found to be a necessary host factor for dengue and Zika virus replication in mosquito cells. Transcription analysis of infected mosquito cells silenced for DIDO1 revealed alterations of the IMD and Toll pathways, part of the antiviral response in mosquitoes. The results suggest that DIDO1 is a host factor involved in modulation of the antiviral response and necessary for flavivirus replication.

Ant Venom-Based Ceramide Therapy Is Effective Against Atopic Dermatitis In Vivo.

BACKGROUND: Atopic dermatitis (AD) is a common skin condition with relatively few therapeutic alternatives. These include corticosteroids, which address inflammation but not superinfection, and Januse kinase (JAK) inhibitors, which have a US Food and Drug Administration (FDA) black box for potential carcinogenicity. METHODS: We demonstrate that S14, a synthetic derivative of ant venom-derived solenopsin, has potent anti inflammatory effects on the OVA murine model of atopic dermatitis. S14 has demonstrated prior activity in murine psoriasis and has the benefit of ceramide anti-inflammatory effects without being able to be metabolized into proinflammatory sphingosine-1 phosphate. RESULTS: The efficacy of S14 accompanied by the induction of IL-12 suggests a commonality in inflammatory skin disorders, and our results suggest that pharmacological ceramide restoration will be broadly effective for inflammatory skin disease. CONCLUSIONS: Solenopsin derivative S14 has anti-inflammatory effects in murine models of AD and psoriasis. This makes S14 a strong candidate for human use, and pre-IND studies are warranted.J Drugs Dermatol. 2023;22(10):1001-1006 doi:10.36849/JDD.7308.

Single-cell transcriptome profile of mouse skin undergoing antigen-driven allergic inflammation recapitulates findings in atopic dermatitis skin lesions.

BACKGROUND: Allergic skin inflammation elicited in mice by epicutaneous (EC) sensitization with antigen shares characteristics with human atopic dermatitis (AD). OBJECTIVE: We characterized gene expression by single cells in mouse skin undergoing antigen-driven allergic inflammation and compared the results with findings in AD skin lesions. METHODS: Mice were EC sensitized by application of ovalbumin (OVA) or saline to tape-stripped skin. Single-cell RNA sequencing was performed on skin cells 12 days later. Flow cytometry analysis was performed to validate results. RESULTS: Sequencing identified 7 nonhematopoietic and 6 hematopoietic cell subsets in EC-sensitized mouse skin. OVA sensitization resulted in the expansion in the skin of T cells, dendritic cells, macrophages, mast cells/basophils, fibroblasts, and myocytes cell clusters, and in upregulation of TH2 cytokine gene expression in CD4+ T cells and mast cells/basophils. Genes differentially expressed in OVA-sensitized skin included genes important for inflammation in dendritic cells and macrophages, collagen deposition, and leukocyte migration in fibroblasts, chemotaxis in endothelial cells and skin barrier integrity, and differentiation in KCs-findings that recapitulate those in AD skin lesions. Unexpectedly, mast cells/basophils, rather than T cells, were the major source of Il4 and ll13 in OVA-sensitized mouse skin. In addition, our results suggest novel pathways in fibroblast and endothelial cells that may contribute to allergic skin inflammation. CONCLUSION: The gene expression profile of single cells in mouse skin undergoing antigen-driven shares many features with that in AD skin lesions and unveils novel pathways that may be involved in allergic skin inflammation.

Mast cell-derived IL-13 downregulates IL-12 production by skin dendritic cells to inhibit the TH1 cell response to cutaneous antigen exposure.

BACKGROUND: Atopic dermatitis (AD) is characterized by a skin barrier defect aggravated by mechanical injury inflicted by scratching, a TH2 cell-dominated immune response, and susceptibility to viral skin infections that are normally restrained by a TH1 cell response. The signals leading to a TH2 cell-dominated immune response in AD are not completely understood. OBJECTIVE: Our aim was to determine the role of IL-13 in initiation of the TH cell response to cutaneously encountered antigens. METHODS: Wild-type, Il13-/-, Il1rl1-/-, and Il4ra-/- mice, as well as mice with selective deficiency of IL-13 in mast cells (MCs) were studied; in addition, dendritic cells (DCs) purified from the draining lymph nodes of tape-stripped and ovalbumin (OVA)-sensitized skin were examined for their ability to polarize naive OVA-TCR transgenic CD4+ T cells. Cytokine expression was examined by reverse-transcriptase quantitative PCR, intracellular flow cytometry, and ELISA. Contact hypersensitivity to dinitrofluorobenzene was examined. RESULTS: Tape stripping caused IL-33-driven upregulation of Il13 expression by skin MCs. MC-derived IL-13 acted on DCs from draining lymph nodes of OVA-sensitized skin to selectively suppress their ability to polarize naive OVA-TCR transgenic CD4+ T cells into IFN-γ-secreting cells. MC-derived IL-13 inhibited the TH1 cell response in contact hypersensitivity to dinitrofluorobenzene. IL-13 suppressed IL-12 production by mouse skin-derived DCs in vitro and in vivo. Scratching upregulated IL13 expression in human skin, and IL-13 suppressed the capacity of LPS-stimulated human skin DCs to express IL-12 and promote IFN-γ secretion by CD4+ T cells. CONCLUSION: Release of IL-13 by cutaneous MCs in response to mechanical skin injury inhibits the TH1 cell response to cutaneous antigen exposure in AD.

ILC2 activation by keratinocyte-derived IL-25 drives IL-13 production at sites of allergic skin inflammation.

BACKGROUND: Atopic dermatitis skin lesions demonstrate increased expression of IL-25 by keratinocytes and increased numbers of type 2 innate lymphoid cells (ILC2s) that express high levels of IL-25 receptor (IL-25R). IL-13 is expressed in atopic dermatitis skin lesions and plays an important role in pathogenesis of the disease. OBJECTIVE: Our aim was to determine the role of IL-25 and ILC2s in a mouse model of antigen-driven allergic skin inflammation. METHODS: Wild-type mice; mice that express an Il13-driven enhanced green fluorescent protein; and mice that lack IL-25R, IL-25 in keratinocytes, or IL-13 or IL-25R in ILC2s were subjected to acute or chronic epicutaneous sensitization with ovalbumin. Sensitized skin was examined by histology for epidermal thickening. Cellular infiltrates were analyzed for surface markers and intracellular expression of enhanced green fluorescent protein by flow cytometry. Gene expression was quantitated by RT quantitative PCR. RESULT: In both acute and chronic antigen-driven allergic skin inflammation, signaling by keratinocyte-derived IL-25 in ILC2s is important for epidermal hyperplasia, dermal infiltration by CD4+ T cells, and cutaneous expression of Il13 and the IL-13-dependent TH2-cell-attracting chemokines Cc17 and Ccl22. ILCs are the major source of IL-13 in acutely sensitized mouse skin, whereas T cells are its major source in chronically sensitized mouse skin. CONCLUSION: ILC2 activation by IL-25 is essential for IL-13 expression at sites of allergic skin inflammation.

Allergic skin inflammation and S. aureus skin colonization are mutually reinforcing.

Atopic dermatitis (AD) lesional skin is often colonized with S. aureus, and the load of S. aureus correlates with disease severity. However, a causative and mechanistic link between S. aureus skin colonization and severity of AD is not well established. We made use of well-established mouse model of AD elicited by epicutaneous sensitization of tape stripped skin with ovalbumin to investigate the relationship between allergic skin inflammation and cutaneous S. aureus colonization. Topical application of S aureus exacerbated allergic skin inflammation induced by epicutaneous sensitization with ovalbumin, whereas allergic skin inflammation generated a permissive environment for S. aureus persistence. Our results establish a mutually reinforcing role of allergic skin inflammation and S. aureus skin colonization.

APRIL expression is upregulated in atopic dermatitis skin lesions and at sites of antigen driven allergic skin inflammation in mice.

Atopic dermatitis (AD) is the most common inflammatory skin disease. It is characterized by a defective skin barrier and a Th2 dominated skin inflammation. The TNF family member a proliferation-inducing ligand (APRIL) and its receptors transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) and B cell maturation antigen (BCMA) are expressed by immune cells and epithelial cells including keratinocytes. We demonstrate that APRIL expression is upregulated in the epidermis of skin lesions from patients with AD as well as in mouse skin undergoing allergic inflammation elicited by epicutaneous (EC) sensitization with the antigen ovalbumin. We show that APRIL from OVA sensitized mouse skin causes keratinocytes to upregulate the expression of IL-6, an inflammatory cytokine implicated in AD pathogenesis. These results suggest a role for APRIL in allergic skin inflammation and a potential role for APRIL blockade in treating AD.

IL-22 promotes allergic airway inflammation in epicutaneously sensitized mice.

BACKGROUND: Serum IL-22 levels are increased in patients with atopic dermatitis, which commonly precedes asthma in the atopic march. Epicutaneous sensitization in mice results in TH2-dominated skin inflammation that mimics atopic dermatitis and sensitizes the airways for antigen challenge-induced allergic inflammation characterized by the presence of both eosinophils and neutrophils. Epicutaneous sensitization results in increased serum levels of IL-22. OBJECTIVE: We sought to determine the role of IL-22 in antigen-driven airway allergic inflammation after inhalation challenge in epicutaneously sensitized mice. METHODS: Wild-type (WT) and Il22-/- mice were sensitized epicutaneously or immunized intraperitoneally with ovalbumin (OVA) and challenged intranasally with antigen. OVA T-cell receptor-specific T cells were TH22 polarized in vitro. Airway inflammation, mRNA levels in the lungs, and airway hyperresponsiveness (AHR) were examined. RESULTS: Epicutaneous sensitization preferentially elicited an IL-22 response compared with intraperitoneal immunization. Intranasal challenge of mice epicutaneously sensitized with OVA elicited in the lungs Il22 mRNA expression, IL-22 production, and accumulation of CD3+CD4+IL-22+ T cells that coexpressed IL-17A and TNF-α. Epicutaneously sensitized Il22-/- mice exhibited diminished eosinophil and neutrophil airway infiltration and decreased AHR after intranasal OVA challenge. Production of IL-13, IL-17A, and TNF-α was normal, but IFN-γ production was increased in lung cells from airway-challenged and epicutaneously sensitized Il22-/- mice. Intranasal instillation of IFN-γ-neutralizing antibody partially reversed the defect in eosinophil recruitment. WT recipients of TH22-polarized WT, but not IL-22-deficient, T-cell receptor OVA-specific T cells, which secrete both IL-17A and TNF-α, had neutrophil-dominated airway inflammation and AHR on intranasal OVA challenge. Intranasal instillation of IL-22 with TNF-α, but not IL-17A, elicited neutrophil-dominated airway inflammation and AHR in WT mice, suggesting that loss of IL-22 synergy with TNF-α contributed to defective recruitment of neutrophils into the airways of Il22-/- mice. TNF-α, but not IL-22, blockade at the time of antigen inhalation challenge inhibited airway inflammation in epicutaneously sensitized mice. CONCLUSION: Epicutaneous sensitization promotes generation of antigen-specific IL-22-producing T cells that promote airway inflammation and AHR after antigen challenge, suggesting that IL-22 plays an important role in the atopic march.

Survival After Ischemic and Hemorrhagic Stroke: A 4-Year Follow-Up at a Mexican Hospital.

BACKGROUND: Overall, 75.2% of deaths from stroke occur in low- and middle-income countries. Mexico is a middle-income country with little information about the prognosis of early and late postischemic and hemorrhagic stroke. OBJECTIVE: To evaluate the factors associated with post-stroke survival in the Mexican population. METHODS: Observational study of consecutive stroke cases involving a first-ever hemorrhagic or ischemic stroke, with patients who received care at the National Institute of Neurology and Neurosurgery, in Mexico City, between 2009 and 2012. Patients were followed for up to 4 years after the index event. Exploratory analysis of survival was carried out with Kaplan-Meier and log-rank tests. Factors associated with survival time were determined using Cox models. RESULTS: A total of 300 out of 544 (55.15%) patients had a hemorrhagic stroke, 135 of 544 (24.82%) patients died during the entire follow-up period, and 56 of 544 (10.29%) died in the first 30 days post-stroke (early mortality). Early mortality after stroke was associated with age ≥ 65 years (Adjusted Hazard Ratio - AHR = 2.07, P = .02) and ≥ 2 in-hospital medical complications (AHR = 46.13, P < .01). Late mortality was associated with age ≥ 65 years (AHR = 3.43, P < .01), ≥2 in-hospital medical complications (AHR = 2.55, P < .01), high comorbidity (AHR = 5.43, P < .01), and recurrence (AHR = 1.90, P = .01). CONCLUSIONS: Patients with hemorrhagic and ischemic stroke who presented in-hospital medical complications, high comorbidity, and were over 65 years old had higher rates of early and late mortality.

Influence of bidisperse self-assembled monolayer structure on the slip boundary condition of thin polymer films.

Alkylsilane self-assembled monolayers (SAMs) are often used as model substrates for their ease of preparation and hydrophobic properties. We have observed that these atomically smooth monolayers also provide a slip boundary condition for dewetting films composed of unentangled polymers. This slip length, an indirect measure of the friction between a given liquid and different solids, is switchable and can be increased [R. Fetzer et al., Phys. Rev. Lett. 95, 127801 (2005); O. Bäumchen et al., J. Phys.: Condens. Matter 24, 325102 (2012)] if the alkyl chain length is changed from 18 to 12 backbone carbons, for example. Typically, this change in boundary condition is affected in a quantized way, using one or the other alkyl chain length, thus obtaining one or the other slip length. Here, we present results in which this SAM structure is changed in a continuous way. We prepare bidisperse mixed SAMs of alkyl silanes, with the composition as a control parameter. We find that all the mixed SAMs investigated show an enhanced slip boundary condition as compared to the single-component SAMs. The slip boundary condition is accessed using optical and atomic force microscopy, and we describe these observations in the context of X-ray reflectivity measurements. The slip length, varying over nearly two orders of magnitude, of identical polymer melts on chemically similar SAMs is found to correlate with the density of exposed alkyl chains. Our results demonstrate the importance of a well characterized solid/liquid pair, down to the angstrom level, when discussing the friction between a liquid and a solid.