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1.
J Immunol ; 207(12): 3098-3106, 2021 12 15.
Artículo en Inglés | MEDLINE | ID: mdl-34799426

RESUMEN

Rodent mast cells are classified into two major subsets, mucosal mast cells (MMCs) and connective tissue mast cells. MMCs arise from mast cell progenitors that are mobilized from the bone marrow to mucosal tissues in response to allergic inflammation or helminth infection. TGF-ß is known as an inducer of MMC differentiation in mucosal tissues, but we have previously found that Notch receptor-mediated signaling also leads to the differentiation. Here, we examined the relationship between Notch and TGF-ß signaling in MMC differentiation using mouse bone marrow-derived mast cells (BMMCs). We found that the coexistence of Notch and TGF-ß signaling markedly upregulates the expression of MMC markers, mouse mast cell protease (mMCP)-1, mMCP-2, and αE integrin/CD103, more than Notch or TGF-ß signaling alone, and that their signals act interdependently to induce these marker expressions. Notch and TGF-ß-mediated transcription of MMC marker genes were both dependent on the TGF-ß signaling transducer SMAD4. In addition, we also found that Notch signaling markedly upregulated mMCP-1 and mMCP-2 expression levels through epigenetic deregulation of the promoter regions of these genes, but did not affect the promoter of the CD103-encoding gene. Moreover, forced expression of the constitutively active Notch2 intracellular domain in BMMCs showed that Notch signaling promotes the nuclear localization of SMADs 3 and 4 and causes SMAD4-dependent gene transcription. These findings indicate that Notch and TGF-ß signaling play interdependent roles in inducing the differentiation and maturation of MMCs. These roles may contribute to the rapid expansion of the number of MMCs during allergic mucosal inflammation.


Asunto(s)
Mastocitos , Factor de Crecimiento Transformador beta , Animales , Expresión Génica , Inflamación/metabolismo , Mastocitos/metabolismo , Ratones , Membrana Mucosa , Factor de Crecimiento Transformador beta/metabolismo
2.
Int J Mol Sci ; 24(11)2023 May 27.
Artículo en Inglés | MEDLINE | ID: mdl-37298299

RESUMEN

Atopic dermatitis and psoriasis are prevalent chronic inflammatory skin diseases that are characterized by dysfunctional skin barriers and substantially impact patients' quality of life. Vitamin D3 regulates immune responses and keratinocyte differentiation and improves psoriasis symptoms; however, its effects on atopic dermatitis remain unclear. Here, we investigated the effects of calcitriol, an active form of vitamin D3, on an NC/Nga mouse model of atopic dermatitis. We observed that the topical application of calcitriol decreased the dermatitis scores and epidermal thickness of NC/Nga mice with atopic dermatitis compared to untreated mice. In addition, both stratum corneum barrier function as assessed by the measurement of transepidermal water loss and tight junction barrier function as evaluated by biotin tracer permeability assay were improved following calcitriol treatment. Moreover, calcitriol treatment reversed the decrease in the expression of skin barrier-related proteins and decreased the expression of inflammatory cytokines such as interleukin (IL)-13 and IL-33 in mice with atopic dermatitis. These findings suggest that the topical application of calcitriol might improve the symptoms of atopic dermatitis by repairing the dysfunctional epidermal and tight junction barriers. Our results suggest that calcitriol might be a viable therapeutic agent for the treatment of atopic dermatitis in addition to psoriasis.


Asunto(s)
Dermatitis Atópica , Psoriasis , Ratones , Animales , Dermatitis Atópica/metabolismo , Calcitriol/uso terapéutico , Colecalciferol/farmacología , Calidad de Vida , Piel/metabolismo , Citocinas/metabolismo , Interleucina-13/metabolismo , Psoriasis/tratamiento farmacológico , Psoriasis/metabolismo , Modelos Animales de Enfermedad
3.
Int J Mol Sci ; 24(6)2023 Mar 08.
Artículo en Inglés | MEDLINE | ID: mdl-36982275

RESUMEN

The antimicrobial peptide derived from insulin-like growth factor-binding protein 5 (AMP-IBP5) exhibits antimicrobial activities and immunomodulatory functions in keratinocytes and fibroblasts. However, its role in regulating skin barrier function remains unclear. Here, we investigated the effects of AMP-IBP5 on the skin barrier and its role in the pathogenesis of atopic dermatitis (AD). 2,4-Dinitrochlorobenzene was used to induce AD-like skin inflammation. Transepithelial electrical resistance and permeability assays were used to investigate tight junction (TJ) barrier function in normal human epidermal keratinocytes and mice. AMP-IBP5 increased the expression of TJ-related proteins and their distribution along the intercellular borders. AMP-IBP5 also improved TJ barrier function through activation of the atypical protein kinase C and Rac1 pathways. In AD mice, AMP-IBP5 ameliorated dermatitis-like symptoms restored the expression of TJ-related proteins, suppressed the expression of inflammatory and pruritic cytokines, and improved skin barrier function. Interestingly, the ability of AMP-IBP5 to alleviate inflammation and improve skin barrier function in AD mice was abolished in mice treated with an antagonist of the low-density lipoprotein receptor-related protein-1 (LRP1) receptor. Collectively, these findings indicate that AMP-IBP5 may ameliorate AD-like inflammation and enhance skin barrier function through LRP1, suggesting a possible role for AMP-IBP5 in the treatment of AD.


Asunto(s)
Dermatitis Atópica , Humanos , Animales , Ratones , Dermatitis Atópica/inducido químicamente , Dermatitis Atópica/tratamiento farmacológico , Dermatitis Atópica/metabolismo , Péptidos Antimicrobianos , Queratinocitos/metabolismo , Inflamación/metabolismo , Citocinas/metabolismo , Modelos Animales de Enfermedad , Lipoproteínas LDL/metabolismo , Piel/metabolismo
4.
J Clin Immunol ; 42(5): 1009-1025, 2022 07.
Artículo en Inglés | MEDLINE | ID: mdl-35420364

RESUMEN

PURPOSE: Although mast cells (MCs) modulate the activity of effector cells during Candida albicans infection, their role in the pathogenesis of candidiasis remains unclear. Candidalysin, a C. albicans-derived peptide toxin, is a crucial factor in fungal infections. We aimed to investigate the effect of candidalysin on MC activation and the underlying molecular mechanism. METHODS: Serum from candidalysin-immunized mice was used to measure candidalysin expression in patients infected with C. albicans. MC degranulation and migration were evaluated by ß-hexosaminidase release assay and chemotaxis assay, respectively. EIA and ELISA were used to evaluate the production of eicosanoids and cytokines/chemokines, respectively. The production of nitric oxide (NO) was measured with a DAF-FM diacetate kit, while reactive oxygen species (ROS) production was analyzed by flow cytometry. MAPK activation was evaluated by Western blotting. RESULTS: We detected high candidalysin expression in the lesions of patients infected with C. albicans, and the MC number was increased in these lesions. LL-37 colocalized with MCs in the lesions of candidiasis patients. Candidalysin-enhanced MC accumulation in mice and treating LAD2 and HMC-1 cells with candidalysin induced their degranulation, migration, and production of pro- and anti-inflammatory cytokines/chemokines, eicosanoids, ROS, NO, and LL-37. Interestingly, C. albicans strains lacking candidalysin failed to induce MC activation. Moreover, candidalysin increased dectin-1 expression, and the inhibition of dectin-1 decreased MC activation. Downstream dectin-1 signaling involved the MAPK pathways. CONCLUSION: The finding that candidalysin causes cutaneous MC activation may improve our understanding of the role of MCs in the pathology of cutaneous C. albicans infection.


Asunto(s)
Candida albicans , Candidiasis , Animales , Candida albicans/metabolismo , Citocinas/metabolismo , Eicosanoides/metabolismo , Proteínas Fúngicas , Humanos , Lectinas Tipo C , Mastocitos/metabolismo , Ratones , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal , Factores de Virulencia/metabolismo
5.
Int Arch Allergy Immunol ; 183(10): 1040-1049, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35933977

RESUMEN

INTRODUCTION: Repeated skin contact to detergents causes chronic irritant contact dermatitis (ICD) associated with itch sensation and eczema. However, the mechanisms of detergent-induced ICD are poorly understood. Here, we established a new murine model of detergent-induced ICD with H1-antihistamine-refractory itch. METHODS: Ear skin of wild-type and mast cell-deficient mice on the C57BL/6 genetic background was treated with a detergent, sodium dodecyl/lauryl sulfate (SDS), daily for approximately 2 weeks with or without administration of an H1-antihistamine, fexofenadine. Skin inflammation, barrier dysfunction, and itching were analyzed. Quantitative PCR for earlobe gene expression and flow cytometry analysis for draining lymph node cells were conducted. RESULTS: SDS treatment induced skin inflammation with ear swelling, increased transepidermal water loss, and hind-paw scratching behaviors in the wild-type and mast cell-deficient mice. The peak value of scratching bouts was retained for at least 48 h after the last SDS treatment. H1-antihistamine administration showed no or little reduction in the responses. SDS treatment upregulated gene expression for a Th2 cytokine IL-4 and Th17/Th22 cytokines, IL-17A, IL-17F, and IL-22, and increased cell numbers in draining lymph nodes of CD4+ T, CD8+ T, and γδT cells with enhanced expression of GATA3, RORγt, T-bet, or FOXP3 compared with untreated mice. CONCLUSIONS: The present study showed that SDS treatment of ear skin in C57BL/6 mice induces mast cell-independent skin inflammation with H1-antihistamine-refractory itch and suggested a possible Th cytokine- and/or lymphocyte-mediated regulation of the model. The model would be useful for elucidation of mechanisms for inflammation with H1-antihistamine-refractory itch in detergent-induced ICD.


Asunto(s)
Dermatitis , Interleucina-17 , Animales , Ratones , Citocinas/genética , Citocinas/metabolismo , Detergentes/metabolismo , Detergentes/farmacología , Factores de Transcripción Forkhead/genética , Expresión Génica , Antagonistas de los Receptores Histamínicos , Inflamación/metabolismo , Interleucina-17/metabolismo , Interleucina-4/genética , Interleucina-4/metabolismo , Irritantes/metabolismo , Irritantes/farmacología , Ratones Endogámicos C57BL , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/genética , Prurito/tratamiento farmacológico , Prurito/metabolismo , Piel/metabolismo , Sodio/metabolismo , Sodio/farmacología , Agua/metabolismo , Agua/farmacología , Linfocitos T Colaboradores-Inductores
6.
Wound Repair Regen ; 30(2): 232-244, 2022 03.
Artículo en Inglés | MEDLINE | ID: mdl-35092133

RESUMEN

Impaired keratinocyte functions are major factors that are responsible for delayed diabetic wound healing. In addition to its antimicrobial activity, the antimicrobial peptide derived from insulin-like growth factor-binding protein 5 (AMP-IBP5) activates mast cells and promotes keratinocyte and fibroblast proliferation and migration. However, its effects on diabetic wound healing remain unclear. Human keratinocytes were cultured in normal or high glucose milieus. The production of angiogenic growth factor and cell proliferation and migration were evaluated. Wounds in normal and streptozotocin-induced diabetic mice were monitored and histologically examined. We found that AMP-IBP5 rescued the high glucose-induced attenuation of proliferation and migration as well as the production of angiogenin and vascular endothelial growth factors in keratinocytes. The AMP-IBP5-induced activity was mediated by the epidermal growth factor receptor, signal transducer and activator of transcription 1 and 3, and mitogen-activated protein kinase pathways, as indicated by the inhibitory effects of pathway-specific inhibitors. In vivo, AMP-IBP5 markedly accelerated wound healing, increased the expression of angiogenic factors and promoted vessel formation in both normal and diabetic mice. Overall, the finding that AMP-IBP5 accelerated diabetic wound healing by protecting against glucotoxicity and promoting angiogenesis suggests that AMP-IBP5 might be a potential therapeutic target for treating chronic diabetic wounds.


Asunto(s)
Diabetes Mellitus Experimental , Somatomedinas , Animales , Ratones , Péptidos Antimicrobianos , Movimiento Celular , Diabetes Mellitus Experimental/metabolismo , Glucosa/farmacología , Queratinocitos , Somatomedinas/metabolismo , Somatomedinas/farmacología , Cicatrización de Heridas
7.
J Allergy Clin Immunol ; 147(3): 1063-1076.e9, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-32717254

RESUMEN

BACKGROUND: Oral immunotherapy (OIT) aims to establish desensitization and sustained unresponsiveness (SU) in patients with food allergy by ingestion of gradually increasing doses of specific food allergens. However, little is known about the mechanisms by which OIT induces SU to specific allergens. OBJECTIVES: We investigated the role of Notch signaling, which controls cell fate decisions in many types of immune cells in the induction of SU by OIT treatment. METHODS: Two types of mouse models, ovalbumin-induced food allergy and OIT, were generated. To elucidate the role of Notch signaling in OIT-induced SU, mice were intraperitoneally injected with the Notch signaling inhibitor N-[(3,5-difluorophenyl)acetyl]-l-alanyl-2-phenylglycine-1,1-dimethylethyl ester during the OIT treatment period. RESULTS: Ovalbumin-sensitized mice were desensitized and also had SU induced by OIT treatment, whereas repeated challenges with ovalbumin caused the development of severe allergic reactions in ovalbumin-sensitized mice. Administration of N-[(3,5-difluorophenyl)acetyl]-l-alanyl-2-phenylglycine-1,1-dimethylethyl ester to mice during the OIT treatment period inhibited the establishment of SU to ovalbumin but did not affect the induction of desensitization. OIT induced a systemic expansion of IL-10-producing CD4+ T cells, including TH2 cells, and myeloid-derived suppressor cells (MDSCs), particularly the monocytic MDSC subpopulation. Inhibition of Notch signaling prevented the OIT-induced expansion of those cells. In vitro cultures of bone marrow cells showed that Notch signaling directly promoted the generation of monocytic MDSCs. In addition, the contribution of MDSCs to OIT-induced SU was confirmed by MDSC depletion with the anti-Gr1 antibody. CONCLUSION: Notch signaling contributes to the establishment of SU induced by OIT through systemic expansion of immunosuppressive cells, such as IL-10-producing CD4+ T cells and MDSCs.


Asunto(s)
Desensibilización Inmunológica/métodos , Hipersensibilidad a los Alimentos/inmunología , Células Supresoras de Origen Mieloide/inmunología , Receptores Notch/metabolismo , Células Th2/inmunología , Administración Oral , Alérgenos/inmunología , Animales , Células Cultivadas , Modelos Animales de Enfermedad , Femenino , Hipersensibilidad a los Alimentos/terapia , Humanos , Tolerancia Inmunológica , Interleucina-10/metabolismo , Ratones , Ratones Endogámicos BALB C , Ovalbúmina/inmunología , Transducción de Señal
8.
Int J Mol Sci ; 23(15)2022 Aug 08.
Artículo en Inglés | MEDLINE | ID: mdl-35955934

RESUMEN

The skin produces a plethora of antimicrobial peptides that not only show antimicrobial activities against pathogens but also exhibit various immunomodulatory functions. Human ß-defensins (hBDs) are the most well-characterized skin-derived antimicrobial peptides and contribute to diverse biological processes, including cytokine production and the migration, proliferation, and differentiation of host cells. Additionally, hBD-3 was recently reported to promote wound healing and angiogenesis, by inducing the expression of various angiogenic factors and the migration and proliferation of fibroblasts. Angiogenin is one of the most potent angiogenic factors; however, the effects of hBDs on angiogenin production in fibroblasts remain unclear. Here, we investigated the effects of hBDs on the secretion of angiogenin by human dermal fibroblasts. Both in vitro and ex vivo studies demonstrated that hBD-1, hBD-2, hBD-3, and hBD-4 dose-dependently increased angiogenin production by fibroblasts. hBD-mediated angiogenin secretion involved the epidermal growth factor receptor (EGFR), Src family kinase, c-Jun N-terminal kinase (JNK), p38, and nuclear factor-kappa B (NF-κB) pathways, as evidenced by the inhibitory effects of specific inhibitors for these pathways. Indeed, we confirmed that hBDs induced the activation of the EGFR, Src, JNK, p38, and NF-κB pathways. This study identified a novel role of hBDs in angiogenesis, through the production of angiogenin, in addition to their antimicrobial activities and other immunomodulatory properties.


Asunto(s)
Antiinfecciosos , beta-Defensinas , Antiinfecciosos/farmacología , Péptidos Antimicrobianos , Células Cultivadas , Receptores ErbB , Fibroblastos/metabolismo , Humanos , FN-kappa B/metabolismo , Ribonucleasa Pancreática , beta-Defensinas/metabolismo
9.
Int J Mol Sci ; 23(19)2022 Sep 29.
Artículo en Inglés | MEDLINE | ID: mdl-36232814

RESUMEN

Betacellulin (BTC) is a peptide ligand that belongs to the epidermal growth factor family, the members of which have been implicated in skin morphogenesis, homeostasis, repair, and angiogenesis; however, the role of BTC in the regulation of the skin barrier remains unknown. To examine the role of BTC in skin barrier function, we analyzed atopic dermatitis (AD) transcriptomic data from Gene Expression Omnibus (GEO) datasets, performed BTC immunohistochemistry using human skin tissues, and evaluated the effects of BTC on primary human keratinocytes by real-time PCR, Western blotting, and assay of the transepidermal electrical resistance (TER), a functional parameter to monitor the tight junction barrier. We found that the gene expression of BTC was downregulated in skin lesions from patients with AD, and this downregulated expression recovered following biological treatments. Consistently, the BTC protein levels were downregulated in the lesional skin of AD patients compared with the normal skin of healthy participants, suggesting that the BTC levels in skin might be a biomarker for the diagnosis and therapy of AD. Furthermore, in human keratinocytes, BTC knockdown reduced the levels of skin-derived antimicrobial peptides and skin barrier-related genes, whereas BTC addition enhanced their levels. Importantly, in human skin equivalents, BTC restored the increased tight junction permeability induced by Th2 cytokine IL-4/IL-13 treatment. In addition, specific inhibitors of epidermal growth factor receptor (EGFR) and protein kinase C (PKC) abolished the BTC-mediated improvement in skin barrier-related proteins in keratinocyte monolayers. Collectively, our findings suggest that treatment with BTC might improve the Th2-type cytokine-mediated impairment of skin barrier function through the EGFR/PKC axis and that BTC might be a novel potential biomarker and therapeutic target for the treatment of skin conditions characterized by the overproduction of Th2 cytokines and dysfunctional skin barriers, such as AD.


Asunto(s)
Citocinas , Dermatitis Atópica , Betacelulina/metabolismo , Citocinas/metabolismo , Dermatitis Atópica/metabolismo , Receptores ErbB/genética , Receptores ErbB/metabolismo , Humanos , Interleucina-13/metabolismo , Interleucina-13/farmacología , Interleucina-4/metabolismo , Queratinocitos/metabolismo , Ligandos , Proteína Quinasa C/metabolismo , Piel/metabolismo
10.
Biochem Biophys Res Commun ; 569: 86-92, 2021 09 10.
Artículo en Inglés | MEDLINE | ID: mdl-34237432

RESUMEN

Neutrophils undergo spontaneous apoptosis within 24-48 h after leaving bone marrow. Apoptotic neutrophils are subsequently phagocytosed and cleared by macrophages, thereby maintaining neutrophil homeostasis. Previous studies have demonstrated involvement of lysophosphatidylglucoside (lysoPtdGlc), a degradation product of PtdGlc, in modality-specific repulsive guidance of spinal sensory axons, via its specific receptor GPR55. In the present study, using human monocytic cell line THP-1 as a model, we demonstrated that lysoPtdGlc induces monocyte/macrophage migration with typical bell-haped curve and a peak at concentration 10-9 M. Lysophosphatidylinositol (lysoPtdIns), a known GPR55 ligand, induced migration at higher concentration (10-7 M). LysoPtdGlc-treated cells had a polarized shape, whereas lysoPtdIns-treated cells had a spherical shape. In EZ-TAXIScan (chemotaxis) assay, lysoPtdGlc induced chemotactic migration activity of THP-1 cells, while lysoPtdIns induced random migration activity. GPR55 antagonist ML193 inhibited lysoPtdGlc-induced THP-1 cell migration, whereas lysoPtdIns-induced migration was inhibited by CB2-receptor inverse agonist. SiRNA experiments showed that GPR55 mediated lysoPtdGlc-induced migration, while lysoPtdIns-induced migration was mediated by CB2 receptor. Our findings, taken together, suggest that lysoPtdGlc functions as a chemotactic molecule for human monocytes/macrophages via GPR55 receptor, while lysoPtdIns induces random migration activity via CB2 receptor.


Asunto(s)
Movimiento Celular/efectos de los fármacos , Glucósidos/farmacología , Lisofosfolípidos/química , Macrófagos/efectos de los fármacos , Monocitos/efectos de los fármacos , Receptores de Cannabinoides/metabolismo , Western Blotting , Movimiento Celular/genética , Quimiotaxis/efectos de los fármacos , Quimiotaxis/fisiología , Glucósidos/química , Humanos , Lisofosfolípidos/farmacología , Macrófagos/citología , Macrófagos/metabolismo , Monocitos/citología , Monocitos/metabolismo , Interferencia de ARN , Receptores de Cannabinoides/genética , Células THP-1
11.
Biochem Biophys Res Commun ; 546: 192-199, 2021 03 26.
Artículo en Inglés | MEDLINE | ID: mdl-33618285

RESUMEN

Environmental allergen sources such as house dust mites contain proteases, which are frequently allergens themselves. Inhalation with the exogenous proteases, such as a model of protease allergen, papain, to airways evokes release and activation of IL-33, which promotes innate and adaptive allergic airway inflammation and Th2 sensitization in mice. Here, we examine whether epicutaneous (e.c.) vaccination with antigens with and without protease activity shows prophylactic effect on the Th airway sensitization and Th2-medated airway inflammation, which are driven by exogenous or endogenous IL-33. E.c. vaccination with ovalbumin restrained ovalbumin-specific Th2 airway sensitization and/or airway inflammation on subsequent inhalation with ovalbumin plus papain or ovalbumin plus recombinant IL-33. E.c. vaccination with papain or protease inhibitor-treated papain restrained papain-specific Th2 and Th9 airway sensitization, eosinophilia, and infiltration of IL-33-responsive Th2 and group 2 innate lymphoid cells on subsequent inhalation with papain. However, e.c. vaccination with papain but not protease inhibitor-treated papain induced Th17 response in bronchial draining lymph node cells. In conclusions, we demonstrated that e.c. allergen vaccination via intact skin in mice restrained even protease allergen-activated IL-33-driven airway Th2 sensitization to attenuate allergic airway inflammation and that e.c. vaccination with protease allergen attenuated the airway inflammation similar to its derivative lacking the protease activity, although the former but not the latter promoted Th17 development. In addition, the present study suggests that modified allergens, of which Th17-inducing e.c. adjuvant activity such as the protease activity was eliminated, might be preferable for safer clinical applications of the e.c. allergen administration.


Asunto(s)
Inflamación/inmunología , Ovalbúmina/inmunología , Papaína/antagonistas & inhibidores , Papaína/inmunología , Células Th17 , Células Th2/inmunología , Vacunación/métodos , Administración por Inhalación , Animales , Femenino , Inmunoglobulina E/inmunología , Inflamación/prevención & control , Mediadores de Inflamación/inmunología , Interleucina-33/administración & dosificación , Interleucina-33/inmunología , Ratones , Ovalbúmina/administración & dosificación , Ovalbúmina/sangre , Papaína/administración & dosificación , Células Th17/inmunología
12.
Clin Exp Allergy ; 51(3): 382-392, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33394511

RESUMEN

Atopic dermatitis (AD) is a chronic relapsing inflammatory cutaneous disease that is often associated with other atopic symptoms, such as food allergy, allergic rhinitis and asthma, leading to significant morbidity and healthcare costs. The pathogenesis of AD is complicated and multifactorial. Although the aetiology of AD remains incompletely understood, recent studies have provided further insight into AD pathophysiology, demonstrating that the interaction among genetic predisposition, immune dysfunction and environmental provocation factors contributes to its development. However, the increasing prevalence of AD suggests that environmental factors such as irritation and cutaneous infection play a crucial role in triggering and/or aggravating the disease. Of note, AD skin is susceptible to bacterial, fungal and viral infections, and microorganisms may colonize the skin and aggravate AD symptoms. Overall, understanding the mechanisms by which these risk factors affect the cutaneous immunity of patients with AD is of great importance for developing a precision medicine approach for treatment. This review summarizes recent developments in exogenous factors involved in the pathogenesis of AD, with special emphasis on irritants and microbial infections.


Asunto(s)
Dermatitis Atópica/fisiopatología , Irritantes/efectos adversos , Enfermedades Cutáneas Infecciosas/microbiología , Piel/microbiología , Dermatitis Atópica/inmunología , Dermatitis Atópica/microbiología , Humanos , Erupción Variceliforme de Kaposi/inmunología , Erupción Variceliforme de Kaposi/fisiopatología , Microbiota , Molusco Contagioso/inmunología , Molusco Contagioso/fisiopatología , Enfermedades Cutáneas Infecciosas/inmunología , Enfermedades Cutáneas Infecciosas/fisiopatología
13.
Int Arch Allergy Immunol ; 182(9): 788-799, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33873179

RESUMEN

INTRODUCTION: Epicutaneous (e.c.) allergen exposure is an important route of sensitization toward allergic diseases in the atopic march. Allergen sources such as house dust mites contain proteases that involve in the pathogenesis of allergy. Prostanoids produced via pathways downstream of cyclooxygenases (COXs) regulate immune responses. Here, we demonstrate effects of COX inhibition with nonsteroidal anti-inflammatory drugs (NSAIDs) on e.c. sensitization to protease allergen and subsequent airway inflammation in mice. METHODS: Mice were treated with NSAIDs during e.c. sensitization to a model protease allergen, papain, and/or subsequent intranasal challenge with low-dose papain. Serum antibodies, cytokine production in antigen-restimulated skin or bronchial draining lymph node (DLN) cells, and airway inflammation were analyzed. RESULTS: In e.c. sensitization, treatment with a nonspecific COX inhibitor, indomethacin, promoted serum total and papain-specific IgE response and Th2 and Th17 cytokine production in skin DLN cells. After intranasal challenge, treatment with indomethacin promoted allergic airway inflammation and Th2 and Th17 cytokine production in bronchial DLN cells, which depended modestly or largely on COX inhibition during e.c. sensitization or intranasal challenge, respectively. Co-treatment with COX-1-selective and COX-2-selective inhibitors promoted the skin and bronchial DLN cell Th cytokine responses and airway inflammation more efficiently than treatment with either selective inhibitor. CONCLUSION: The results suggest that the overall effects of COX downstream prostanoids are suppressive for development and expansion of not only Th2 but also, unexpectedly, Th17 upon exposure to protease allergens via skin or airways and allergic airway inflammation.


Asunto(s)
Alérgenos/inmunología , Ciclooxigenasa 1/metabolismo , Ciclooxigenasa 2/metabolismo , Inhibidores de la Ciclooxigenasa/farmacología , Péptido Hidrolasas/inmunología , Células Th17/inmunología , Células Th2/inmunología , Animales , Antiinflamatorios no Esteroideos/farmacología , Diferenciación Celular , Femenino , Inmunización , Ratones , Papaína/inmunología , Hipersensibilidad Respiratoria/inmunología , Hipersensibilidad Respiratoria/metabolismo , Hipersensibilidad Respiratoria/patología , Piel/efectos de los fármacos , Piel/inmunología , Piel/metabolismo , Subgrupos de Linfocitos T/efectos de los fármacos , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Células Th17/efectos de los fármacos , Células Th17/metabolismo , Células Th2/efectos de los fármacos , Células Th2/metabolismo
14.
Int J Mol Sci ; 22(14)2021 Jul 12.
Artículo en Inglés | MEDLINE | ID: mdl-34299063

RESUMEN

Regulatory T cells (Tregs) suppress immune responses and maintain immunological self-tolerance and homeostasis. We currently investigated relationships between skin barrier condition and Treg behavior using skin barrier-disrupted mice. Skin barrier disruption was induced by repeated topical application of 4% sodium dodecyl sulfate (SDS) on mice. The number of CD4+ forkhead box protein P3 (Foxp3)+ Tregs was higher in 4% SDS-treated skins than in controls. This increasing was correlated with the degree of acanthosis. The numbers of interleukin (IL)-10+ and transforming growth factor (TGF)-ß+ Tregs also increased in 4% SDS-treated skins. Localization of IL-33 in keratinocytes shifted from nucleus to cytoplasm after skin barrier disruption. Notably, IL-33 promoted the migration of Tregs in chemotaxis assay. The skin infiltration of Tregs was cancelled in IL-33 neutralizing antibody-treated mice and IL-33 knockout mice. Thus, keratinocyte-derived IL-33 may induce Treg migration into barrier-disrupted skin to control the phase transition between healthy and inflammatory conditions.


Asunto(s)
Movimiento Celular , Quimiotaxis , Dermatitis/patología , Interleucina-33/fisiología , Piel/patología , Linfocitos T Reguladores/inmunología , Animales , Dermatitis/inmunología , Dermatitis/metabolismo , Factores de Transcripción Forkhead/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Piel/metabolismo
15.
Int J Mol Sci ; 21(20)2020 Oct 14.
Artículo en Inglés | MEDLINE | ID: mdl-33066696

RESUMEN

Atopic dermatitis (AD) is a common chronic inflammatory skin disease that exhibits a complex interplay of skin barrier disruption and immune dysregulation. Patients with AD are susceptible to cutaneous infections that may progress to complications, including staphylococcal septicemia. Although most studies have focused on filaggrin mutations, the physical barrier and antimicrobial barrier also play critical roles in the pathogenesis of AD. Within the physical barrier, the stratum corneum and tight junctions play the most important roles. The tight junction barrier is involved in the pathogenesis of AD, as structural and functional defects in tight junctions not only disrupt the physical barrier but also contribute to immunological impairments. Furthermore, antimicrobial peptides, such as LL-37, human b-defensins, and S100A7, improve tight junction barrier function. Recent studies elucidating the pathogenesis of AD have led to the development of barrier repair therapy for skin barrier defects in patients with this disease. This review analyzes the association between skin barrier disruption in patients with AD and antimicrobial peptides to determine the effect of these peptides on skin barrier repair and to consider employing antimicrobial peptides in barrier repair strategies as an additional approach for AD management.


Asunto(s)
Catelicidinas/metabolismo , Defensinas/metabolismo , Dermatitis Atópica/metabolismo , Piel/metabolismo , Cicatrización de Heridas , Dermatitis Atópica/patología , Proteínas Filagrina , Humanos , Piel/patología , Fenómenos Fisiológicos de la Piel
16.
J Biol Chem ; 293(10): 3793-3805, 2018 03 09.
Artículo en Inglés | MEDLINE | ID: mdl-29358324

RESUMEN

CD300 molecules (CD300s) belong to paired activating and inhibitory receptor families, which mediate immune responses. Human CD300e (hCD300e) is expressed in monocytes and myeloid dendritic cells and transmits an immune-activating signal by interacting with DNAX-activating protein 12 (DAP12). However, the CD300e ortholog in mice (mCD300e) is poorly characterized. Here, we found that mCD300e is also an immune-activating receptor. We found that mCD300e engagement triggers cytokine production in mCD300e-transduced bone marrow-derived mast cells (BMMCs). Loss of DAP12 and another signaling protein, FcRγ, did not affect surface expression of transduced mCD300e, but abrogated mCD300e-mediated cytokine production in the BMMCs. Co-immunoprecipitation experiments revealed that mCD300e physically interacts with both FcRγ and DAP12, suggesting that mCD300e delivers an activating signal via these two proteins. Binding and reporter assays with the mCD300e extracellular domain identified sphingomyelin as a ligand of both mCD300e and hCD300e. Notably, the binding of sphingomyelin to mCD300e stimulated cytokine production in the transduced BMMCs in an FcRγ- and DAP12-dependent manner. Flow cytometric analysis with an mCD300e-specific Ab disclosed that mCD300e expression is highly restricted to CD115+Ly-6Clow/int peripheral blood monocytes, corresponding to CD14dim/+CD16+ human nonclassical and intermediate monocytes. Loss of FcRγ or DAP12 lowered the surface expression of endogenous mCD300e in the CD115+Ly-6Clow/int monocytes. Stimulation with sphingomyelin failed to activate the CD115+Ly-6Clow/int mouse monocytes, but induced hCD300e-mediated cytokine production in the CD14dimCD16+ human monocytes. Taken together, these observations indicate that mCD300e recognizes sphingomyelin and thereby regulates nonclassical and intermediate monocyte functions through FcRγ and DAP12.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Mastocitos/metabolismo , Monocitos/metabolismo , Procesamiento Proteico-Postraduccional , Receptores de IgG/metabolismo , Receptores Inmunológicos/agonistas , Esfingomielinas/metabolismo , Proteínas Adaptadoras Transductoras de Señales/química , Proteínas Adaptadoras Transductoras de Señales/genética , Sustitución de Aminoácidos , Animales , Células de la Médula Ósea/citología , Células de la Médula Ósea/inmunología , Células de la Médula Ósea/metabolismo , Línea Celular , Citocinas/metabolismo , Regulación de la Expresión Génica , Células HEK293 , Humanos , Ligandos , Mastocitos/citología , Mastocitos/inmunología , Ratones Endogámicos C57BL , Ratones Noqueados , Monocitos/citología , Monocitos/inmunología , Mutación , Fragmentos de Péptidos/agonistas , Fragmentos de Péptidos/química , Fragmentos de Péptidos/genética , Fragmentos de Péptidos/metabolismo , Dominios y Motivos de Interacción de Proteínas , Multimerización de Proteína , Receptores de IgG/química , Receptores de IgG/genética , Receptores Inmunológicos/química , Receptores Inmunológicos/genética , Receptores Inmunológicos/metabolismo , Proteínas Recombinantes de Fusión/química , Proteínas Recombinantes de Fusión/metabolismo
17.
J Immunol ; 199(8): 2958-2967, 2017 10 15.
Artículo en Inglés | MEDLINE | ID: mdl-28893954

RESUMEN

NR4A3/NOR1 belongs to the NR4A subfamily of the nuclear hormone receptor superfamily, which is activated in a ligand-independent manner. To examine the role of NR4A3 in gene expression of dendritic cells (DCs), we introduced NR4A3 small interfering RNA (siRNA) into bone marrow-derived DCs and determined the expression levels of mRNA and proteins of cytokines, cell surface molecules, NF-κB signaling-related proteins, and transcription factors. The expression level of NR4A3 was markedly upregulated by TLR-mediated stimulation in DCs. NR4A3 knockdown significantly suppressed LPS, CpG, or poly(I:C)-mediated upregulation of CD80, CD86, IL-10, IL-6, and IL-12. Proliferation and IL-2 production levels of T cells cocultured with NR4A3 knocked-down DCs were significantly lower than that of T cells cocultured with control DCs. Furthermore, the expression of IKKß, IRF4, and IRF8 was significantly decreased in NR4A3 siRNA-introduced bone marrow-derived DCs. The knockdown experiments using siRNAs for IKKß, IRF4, and/or IRF8 indicated that LPS-induced upregulation of IL-10 and IL-6 was reduced in IKKß knocked-down cells, and that the upregulation of IL-12 was suppressed by the knockdown of IRF4 and IRF8. Taken together, these results indicate that NR4A3 is involved in TLR-mediated activation and gene expression of DCs.


Asunto(s)
Diferenciación Celular , Proteínas de Unión al ADN/metabolismo , Células Dendríticas/inmunología , Activación de Linfocitos , Proteínas del Tejido Nervioso/metabolismo , Receptores de Esteroides/metabolismo , Receptores de Hormona Tiroidea/metabolismo , Linfocitos T/inmunología , Animales , Presentación de Antígeno , Proliferación Celular , Células Cultivadas , Técnicas de Cocultivo , Proteínas de Unión al ADN/genética , Lipopolisacáridos/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , FN-kappa B/metabolismo , Proteínas del Tejido Nervioso/genética , ARN Interferente Pequeño/genética , Receptores de Esteroides/genética , Receptores de Hormona Tiroidea/genética , Transducción de Señal , Receptores Toll-Like/inmunología
18.
J Biol Chem ; 292(7): 2924-2932, 2017 02 17.
Artículo en Inglés | MEDLINE | ID: mdl-28073916

RESUMEN

LPS triggers inflammatory responses; however, the negative regulation of LPS responses in vivo remains poorly understood. CD300f is an inhibitory receptor among the CD300 family of paired activating and inhibitory receptors. We have previously identified ceramide as a ligand for CD300f and shown that the binding of ceramide to CD300f inhibits IgE-mediated mast cell activation and allergic responses in mouse models. Here we identify the critical role of CD300f in inhibiting LPS-induced skin inflammation. CD300f deficiency remarkably enhanced LPS-induced skin edema and neutrophil recruitment in mice. Higher levels of factors that increase vascular permeability and of factors that induce neutrophil recruitment were detected in LPS-injected skin pouch exudates of CD300f-/- mice as compared with wild-type mice. CD300f was highly expressed in mast cells and recruited neutrophils, but not in macrophages, among skin myeloid cells. CD300f deficiency failed to influence the intrinsic migratory ability of neutrophils. Ceramide-CD300f binding suppressed the release of chemical mediators from mast cells and from neutrophils in response to LPS. Adoptive transfer experiments indicated that mast cells mediated enhanced edema in LPS-stimulated skin of CD300f-/- mice, whereas mast cells together with recruited neutrophils mediated robust neutrophil accumulation. Importantly, administering a ceramide antibody or ceramide-containing vesicles enhanced or suppressed LPS-induced skin inflammation of wild-type mice, respectively. Thus, ceramide-CD300f binding inhibits LPS-induced skin inflammation, implicating CD300f as a negative regulator of Toll-like receptor 4 (TLR4) signaling in vivo.


Asunto(s)
Ceramidas/metabolismo , Dermatitis/prevención & control , Lipopolisacáridos/toxicidad , Receptores Inmunológicos/metabolismo , Animales , Quimiotaxis de Leucocito , Dermatitis/inmunología , Mastocitos/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neutrófilos/inmunología , Receptores Inmunológicos/genética
19.
Int Immunol ; 29(2): 87-94, 2017 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-28338898

RESUMEN

PU.1 is a hematopoietic cell-specific transcription factor belonging to the Ets family, which plays an important role in the development of dendritic cells (DCs). CD11c (encoded by Itgax) is well established as a characteristic marker of hematopoietic lineages including DCs. In the present study, we analyzed the role of PU.1 (encoded by Spi-1) in the expression of CD11c. When small interfering RNA (siRNA) for Spi-1 was introduced into bone marrow-derived DCs (BMDCs), the mRNA level and cell surface expression of CD11c were dramatically reduced. Using reporter assays, the TTCC sequence at -56/-53 was identified to be critical for PU.1-mediated activation of the promoter. An EMSA showed that PU.1 directly bound to this region. ChIP assays demonstrated that a significant amount of PU.1 bound to this region on chromosomal DNA in BMDCs, which was decreased in LPS-stimulated BMDCs in accordance with the reduced levels of mRNAs of Itgax and Spi-1, and the histone acetylation degree. Enforced expression of exogenous PU.1 induced the expression of the CD11c protein on the cell surface of mast cells, whereas control transfectants rarely expressed CD11c. Quantitative RT-PCR also showed that the expression of a transcription factor Irf4, which is a partner molecule of PU.1, was reduced in PU.1-knocked down BMDCs. IRF4 transactivated the Itgax gene in a synergistic manner with PU.1. Taken together, these results indicate that PU.1 functions as a positive regulator of CD11c gene expression by directly binding to the Itgax promoter and through transactivation of the Irf4 gene.


Asunto(s)
Antígeno CD11c/metabolismo , Células Dendríticas/fisiología , Hematopoyesis , Factores Reguladores del Interferón/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Transactivadores/metabolismo , Acetilación , Animales , Antígeno CD11c/genética , Células Cultivadas , Proteínas de Unión al ADN/genética , Regulación de la Expresión Génica , Hematopoyesis/genética , Histonas/metabolismo , Factores Reguladores del Interferón/genética , Ratones , Ratones Endogámicos BALB C , Especificidad de Órganos , Regiones Promotoras Genéticas/genética , Proteínas Proto-Oncogénicas/genética , ARN Interferente Pequeño/genética , Transactivadores/genética , Activación Transcripcional
20.
J Immunol ; 196(9): 3559-69, 2016 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-27001956

RESUMEN

Protease activity of papain, a plant-derived occupational allergen homologous to mite major allergens, is essential to IgE/IgG1 production and lung eosinophilia induced by intranasal papain administration in mice, and IL-33 contributes to these responses. In this work, we investigate skin and Ab responses induced by s.c. papain administration into ear lobes and responses induced by subsequent airway challenge with papain. Subcutaneous papain injection induced swelling associated with increased epidermal thickness, dermal inflammation, serum IgE/IgG1 responses, and Th2 cytokine production in draining lymph node cells restimulated in vitro. These responses were markedly less upon s.c. administration of protease inhibitor-treated papain. Results obtained by using mast cell-deficient mice and reconstitution of tissue mast cells suggested the contribution of mast cells to papain-specific IgE/IgG1 responses and eosinophil infiltration. The responses were equivalent between wild-type and IL-33(-/-) mice. After the subsequent airway challenge, the s.c. presensitized wild-type mice showed more severe lung eosinophilia than those without the presensitization. The presensitized IL-33(-/-) mice showed modest lung eosinophilia, which was absent without the presensitization, but its severity and IgE boost by the airway challenge were markedly less than the presensitized wild-type mice, in which protease activity of inhaled papain contributed to the responses. The results suggest that mechanisms for the protease-dependent sensitization differ between skin and airway and that cooperation of mast cell-dependent, IL-33-independent initial sensitization via skin and protease-induced, IL-33-mediated mechanism in re-exposure via airway to protease allergens maximizes the magnitude of the transition from skin inflammation to asthma in natural history of progression of allergic diseases.


Asunto(s)
Alérgenos/administración & dosificación , Alérgenos/inmunología , Hipersensibilidad/inmunología , Interleucina-33/inmunología , Mastocitos/inmunología , Absorción Nasal , Péptido Hidrolasas/inmunología , Absorción Subcutánea , Animales , Asma , Hiperreactividad Bronquial/inmunología , Hiperreactividad Bronquial/patología , Eosinófilos/inmunología , Hipersensibilidad/patología , Inmunoglobulina E/sangre , Inmunoglobulina G/sangre , Inflamación , Interleucina-33/deficiencia , Pulmón/inmunología , Ratones , Papaína/administración & dosificación , Papaína/inmunología , Péptido Hidrolasas/administración & dosificación , Eosinofilia Pulmonar/inmunología , Eosinofilia Pulmonar/patología , Piel/inmunología , Piel/patología , Células Th2/inmunología
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