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Background: Tick bites often promote local allergic reactions in the skin and predispose to red meat allergy. The mechanisms involved in these processes are not fully understood. Here we investigated the local changes to the skin and intestine induced by tick bites. Methods: C3H/HEN or Balb/c mice were subjected to either tick bites by Ixodes ricinus ( I. ricinus ) or mechanical skin injury. Skin or intestine was analyzed a different time point by transcriptomic and histological techniques. Results: Our results indicate that I. ricinus bites promote epidermal hyperplasia, spongiosis and an accumulation of eosinophils and mast cells in the bitten skin. In addition, I. ricinus bites promote the expression of genes and activate pathways also induced by mechanical skin injury elicited by tape stripping. Remarkably, similar to tape stripping, I. ricinus bites promote an increase in total serum IgE, and intestinal tuft cell and mast cell expansion. Conclusion: I. ricinus bites in mice promote cutaneous inflammation that resembles allergic skin inflammation, as well as intestinal changes that could play a role in the predisposition to red meat allergy.
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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.
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Basófilos , Dermatitis Atópica , Interleucina-4 , Ovalbúmina , Células Th2 , Animales , Basófilos/inmunología , Ratones , Interleucina-4/inmunología , Interleucina-4/genética , Dermatitis Atópica/inmunología , Dermatitis Atópica/patología , Ovalbúmina/inmunología , Células Th2/inmunología , Piel/inmunología , Piel/patología , Ratones Endogámicos C57BL , Ratones Endogámicos BALB C , Modelos Animales de Enfermedad , Células Dendríticas/inmunología , Ratones Transgénicos , Mastocitos/inmunologíaRESUMEN
Physical trauma disrupts skin barrier function. How the skin barrier recovers is not fully understood. We evaluated in mice the mechanism of skin barrier recovery after mechanical injury inflicted by tape stripping. Tape stripping disrupted skin barrier function as evidenced by increased transepidermal water loss. We show that tape stripping induces IL-1-, IL-23-, and TCRγδ+-dependent upregulation of cutaneous Il17a and Il22 expression. We demonstrate that IL-17A and IL-22 induce epidermal hyperplasia, promote neutrophil recruitment, and delay skin barrier function recovery. Neutrophil depletion improved the recovery of skin barrier function and decreased epidermal hyperplasia. Single-cell RNA sequencing and flow cytometry analysis of skin cells revealed basophil infiltration into tape-stripped skin. Basophil depletion upregulated Il17a expression, increased neutrophil infiltration, and delayed skin barrier recovery. Comparative analysis of genes differentially expressed in tape-stripped skin of basophil-depleted mice and Il17a-/- mice indicated that basophils counteract the effects of IL-17A on the expression of epidermal and lipid metabolism genes important for skin barrier integrity. Our results demonstrate that basophils play a protective role by downregulating Il17a expression after mechanical skin injury, thereby counteracting the adverse effect of IL-17A on skin barrier function recovery, and suggest interventions to accelerate this recovery.
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Basófilos , Interleucina-17 , Interleucinas , Animales , Ratones , Basófilos/inmunología , Interleucina-17/metabolismo , Interleucinas/metabolismo , Interleucinas/genética , Piel/lesiones , Piel/patología , Piel/inmunología , Piel/metabolismo , Ratones Noqueados , Modelos Animales de Enfermedad , Interleucina-22 , Pérdida Insensible de Agua/inmunología , Ratones Endogámicos C57BL , Infiltración Neutrófila , Epidermis/lesiones , Epidermis/patología , Epidermis/inmunología , Epidermis/metabolismo , Recuperación de la Función , FemeninoRESUMEN
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.
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Péptido Hidrolasas , Prurito , Receptor PAR-1 , Infecciones Estafilocócicas , Staphylococcus aureus , Animales , Humanos , Ratones , Péptido Hidrolasas/metabolismo , Prurito/microbiología , Receptor PAR-1/metabolismo , Staphylococcus aureus/enzimología , Staphylococcus aureus/patogenicidad , Staphylococcus aureus/fisiología , Infecciones Estafilocócicas/microbiología , Infecciones Estafilocócicas/patologíaRESUMEN
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.
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Antiinfecciosos , Dermatitis Atópica , Ratones , Animales , Dermatitis Atópica/tratamiento farmacológico , Interleucina-17/genética , Ovalbúmina , Inflamación , Piel , Antígenos , Receptores de Interleucina-4 , Ratones Endogámicos BALB CRESUMEN
Aberrant expression of CD43 in malignant tumors of nonhematopoietic origin such as those from lung, cervix, colon, and breast has been shown to correlate with poor prognosis, providing tumor cells with enhanced motility, anchorage-independent growth, and in vivo tumor size, while protecting the cells of NK lysis and apoptosis. To further characterize the role of CD43 in cell transformation, we tested whether interfering its expression modified the capacity of the A549 non-small cell lung cancer cells to secrete molecules contributing to malignancy. The proteomic analysis of the secretome of serum-starved A549 cells revealed that cells expressing normal levels of CD43 released significantly high levels of molecules involved in extracellular matrix organization, angiogenesis, platelet degranulation, collagen degradation, and inflammation, as compared to CD43 RNAi cells. This data reveals a novel and unexpected role for CD43 in lung cancer development, mainly in remodeling the tumor microenvironment.