RESUMEN
Cytokines employ downstream Janus kinases (JAKs) to promote chronic inflammatory diseases. JAK1-dependent type 2 cytokines drive allergic inflammation, and patients with JAK1 gain-of-function (GoF) variants develop atopic dermatitis (AD) and asthma. To explore tissue-specific functions, we inserted a human JAK1 GoF variant (JAK1GoF) into mice and observed the development of spontaneous AD-like skin disease but unexpected resistance to lung inflammation when JAK1GoF expression was restricted to the stroma. We identified a previously unrecognized role for JAK1 in vagal sensory neurons in suppressing airway inflammation. Additionally, expression of Calcb/CGRPß was dependent on JAK1 in the vagus nerve, and CGRPß suppressed group 2 innate lymphoid cell function and allergic airway inflammation. Our findings reveal evolutionarily conserved but distinct functions of JAK1 in sensory neurons across tissues. This biology raises the possibility that therapeutic JAK inhibitors may be further optimized for tissue-specific efficacy to enhance precision medicine in the future.
Asunto(s)
Dermatitis Atópica , Inmunidad Innata , Pulmón , Células Receptoras Sensoriales , Animales , Humanos , Ratones , Citocinas , Dermatitis Atópica/inmunología , Inflamación , Pulmón/inmunología , Linfocitos , Células Receptoras Sensoriales/enzimologíaRESUMEN
Transplantation of solid organs can be life-saving in patients with end-stage organ failure, however, graft rejection remains a major challenge. In this study, by pre-conditioning with interleukin-2 (IL-2)/anti-IL-2 antibody complex treatment biased toward IL-2 receptor α, we achieved acceptance of fully mismatched orthotopic lung allografts that remained morphologically and functionally intact for more than 90 days in immunocompetent mice. These allografts are tolerated by the actions of forkhead box p3 (Foxp3)+ regulatory T (Treg) cells that home to the lung allografts. Although counts of circulating Treg cells rapidly return to baseline following cessation of IL-2 treatment, Foxp3+ Treg cells persist in peribronchial and peribronchiolar areas of the grafted lungs, forming organized clusters reminiscent of inducible tertiary lymphoid structures (iTLS). These iTLS in lung allografts are made of Foxp3+ Treg cells, conventional T cells, and B cells, as evidenced by using microscopy-based distribution and neighborhood analyses. Foxp3-transgenic mice with inducible and selective deletion of Foxp3+ cells are unable to form iTLS in lung allografts, and these mice acutely reject lung allografts. Collectively, we report that short-term, high-intensity and biased IL-2 pre-conditioning facilitates acceptance of vascularized and ventilated lung allografts without the need of immunosuppression, by inducing Foxp3-controlled iTLS formation within allografts.
Asunto(s)
Supervivencia de Injerto , Interleucina-2 , Ratones , Animales , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Pulmón , Rechazo de Injerto , Linfocitos T Reguladores , Ratones Transgénicos , Aloinjertos , Factores de Transcripción ForkheadRESUMEN
Erythropoietic protoporphyria (EPP) is a rare hereditary subtype of cutaneous porphyria characterized by photosensitivity. Increased exposure to light irradiation may precipitate acute liver failure, and surgical light-induced intestinal burns and perforations are known to occur. We report a case of EPP in a patient who underwent laparoscopic partial cecectomy for appendiceal mucocele. A 55-year-old man with EPP was presented for treatment of appendiceal mucocele. A light test using two types of laparoscopes (Companies O and S) was performed preoperatively. Light from the laparoscope manufactured by Company O caused photosensitivity; this effect was not observed with light from the laparoscope manufactured by Company S. Therefore, we performed laparoscopic partial cecectomy through a single umbilical incision using the laparoscope from Company S. Except for the incision site, the patient's skin was completely covered using surgical drapes. No intra- or postoperative complications were observed. Histopathological examination of the resected specimen revealed a low-grade appendiceal mucinous neoplasm.
Asunto(s)
Neoplasias del Apéndice , Laparoscopía , Mucocele , Porfirias , Masculino , Humanos , Persona de Mediana Edad , Mucocele/complicaciones , Mucocele/cirugía , Laparoscopía/efectos adversos , Apendicectomía/efectos adversos , Porfirias/complicaciones , Porfirias/cirugíaRESUMEN
BACKGROUND: Mast cells (MCs) are tissue-resident cells with various immunologic functions. MCs are increased in atopic dermatitis (AD) skin and can contribute to the inflammation. Although skin MCs are inducible from bone marrow (BM) cells in vitro, they are maintained locally by self-proliferation in the steady state in vivo. However, how skin MCs are increased in AD skin, including the infiltration of BM-derived MC progenitors (MCps) and their differentiation, remains unclear. OBJECTIVE: We sought to identify and characterize BM-derived MCps in AD skin. METHODS: BM-derived MCps in AD skin were analyzed by flow cytometry using BM-chimeric mice and parabiosis in an MC903-induced AD model. BM-derived MCps in AD-like skin were compared with resident MCs for gene expression by RNA- sequencing analysis. RESULTS: We observed local proliferation of resident MCs and an increase in BM-derived MCs in AD-like skin. BM-derived MCs in the skin were derived from circulating MCps and were distinguishable from resident MCs by integrinß7. RNA- sequence analysis showed that integrinß7+ MCs (BM-derived MCps) in the skin shared the characteristics of both mucosal-type MCs and connective tissue-type MCs, and increased the expression of genes related to MCp migration. BM-derived MCps proliferated in situ, gradually lost the integrinß7 expression, and acquired connective tissue-type MC phenotypes during the remission phase of inflammation. CONCLUSIONS: BM-derived integrinß7+ MCps migrate to AD-like skin and contribute to the maintenance of skin MCs.
Asunto(s)
Dermatitis Atópica , Ratones , Animales , Dermatitis Atópica/metabolismo , Mastocitos , Médula Ósea/metabolismo , Diferenciación Celular , Inflamación/metabolismo , ARN/metabolismoRESUMEN
BACKGROUND: The circadian rhythm controls multiple biological processes, including immune responses; however, its impact on cutaneous adaptive immune response remains unclear. METHODS: We used a well-established cutaneous type IV allergy model, contact hypersensitivity (CHS). We induced CHS using dinitrofluorobenzene (DNFB). Mice were sensitized and elicited with DNFB in the daytime or at night. RESULTS: In mice, a nocturnally active animal, we found that ear swelling increased when mice were sensitized at night compared with in the daytime. In addition, cell proliferation and cytokine production in the draining lymph nodes (LNs) were promoted when sensitized at night. We hypothesized that these differences were due to the oscillation of leukocyte distribution in the body through the circadian production of adrenergic hormones. Administration of a ß2-adrenergic receptor (ß2AR) agonist salbutamol in the daytime decreased the number of immune cells in blood and increased the number of immune cells in LNs. In contrast, a ß2AR antagonist ICI18551 administration at night increased the number of immune cells in blood and decreased the number of immune cells in LNs. Accordingly, the severity of CHS response was exacerbated by salbutamol administration in the daytime and attenuated by ICI18551 administration at night. CONCLUSION: Our study demonstrated that the magnitude of adaptive CHS response depends on the circadian rhythm and this knowledge may improve the management of allergic contact dermatitis (ACD) in humans.
Asunto(s)
Ritmo Circadiano , Dermatitis Alérgica por Contacto , Albuterol , Animales , Dinitrofluorobenceno , Humanos , Ratones , Ratones Endogámicos BALB C , PielRESUMEN
Decidualization of endometrial stromal cells and the presence of immunocompetent cells, including human mast cells, play important roles in the establishment of pregnancy. In the present study, the effects of decidualization of endometrial stromal cells on the function of decidual mast cells were elucidated. The in vitro assay revealed that decidualization of an endometrial stromal cell line, T HESCs, increased stem cell factor (SCF) mRNA expression. Decidualization of T HESCs enhanced the production of leukemia inhibitory factor (LIF), and the migration of LAD2 cells when co-cultured with T HESCs and LAD2 cells. In addition, decidualization of T HESCs enhanced cell migration in a human trophoblast cell line, HTR-8/SVneo, increased CD9 expression, a marker for extravillous trophoblast (EVT) differentiation, and decreased the secretion of ß human chorionic gonadotropin (hCG), a marker for syncytiotrophoblast (ST) differentiation, when co-cultured with T HESCs, LAD2 cells, and HTR-8/SVneo cells, in a LIF-dependent manner. Histological samples from uterine pregnancies, including decidual stromal cells, showed increased SCF mRNA expression, mast cell numbers and LIF mRNA expression thereof compared with tubal pregnancy. SCF produced by decidual stromal cells enhanced the migration and LIF production of mast cells, and promoted the migration and differentiation of trophoblasts to increase the likelihood of successful human pregnancy.
Asunto(s)
Decidua/metabolismo , Factor Inhibidor de Leucemia/metabolismo , Mastocitos/metabolismo , Factor de Células Madre/metabolismo , Células del Estroma/metabolismo , Adulto , Diferenciación Celular , Línea Celular , Movimiento Celular , Técnicas de Cocultivo , Decidua/citología , Femenino , Humanos , Factor Inhibidor de Leucemia/genética , Embarazo , Trofoblastos/metabolismoRESUMEN
Pruritus is a common dermatological condition and negatively impacts QOL. Persistent pruritus and excessive scratching behavior can lead to the itch-scratch cycle that exacerbates inflammatory skin diseases. Conventional antipruritic drugs, such as antihistamines, corticosteroids, or anticonvulsants, are sometimes insufficient. Recently, however, molecularly targeted drugs, such as IL-31 or IL-4 receptor-targeting antibodies, have become available or are under clinical trials, dramatically changing the clinical situation. In fact, some of these drugs can improve pruritus without the need for topical steroids. Taken together, these observations point to the importance of cytokine-mediated pruritus, further understanding of which may guide improved therapies.
Asunto(s)
Anticuerpos Bloqueadores/uso terapéutico , Antipruriginosos/uso terapéutico , Citocinas/metabolismo , Inmunoterapia/tendencias , Inflamación/terapia , Prurito/terapia , Piel/patología , Animales , Humanos , Inflamación/inmunología , Terapia Molecular Dirigida , Prurito/inmunología , Receptores de Interleucina/inmunología , Receptores de Interleucina-4/inmunologíaRESUMEN
Surfactant-induced cumulative irritant contact dermatitis (ICD) is a common and clinically important skin disorder. CCL2 is known to mediate inflammation after tissue damage in various organs. Thus, we investigated whether and how CCL2 contributes to the development of murine cumulative ICD induced by a common surfactant, SDS. Wild-type mice treated topically with SDS for 6 consecutive days developed skin inflammation that recapitulated the features of human cumulative ICD, including barrier disruption, epidermal thickening, and neutrophil accumulation. CCL2 was upregulated in SDS-treated skin, and local CCL2 blockade attenuated SDS-induced ICD. SDS-induced ICD and neutrophil accumulation were also attenuated in mice deficient in CCR2, the receptor for CCL2. Neutrophil depletion alleviated SDS-induced ICD, suggesting that impaired neutrophil accumulation was responsible for the amelioration of ICD in CCR2-deficient mice. In RNA-sequencing analyses of SDS-treated skin, the expression levels of Il1b in Ccr2-deficient mice were highly downregulated compared with those in wild-type mice. Furthermore, the intradermal administration of IL-1ß in the SDS-treated skin of CCR2-deficient mice restored the local accumulation of neutrophils and the development of ICD. Collectively, our results suggest that CCL2âCCR2 signaling in the skin critically promotes the development of SDS-induced ICD by inducing IL-1ß expression for neutrophil accumulation.
Asunto(s)
Dermatitis Irritante , Neutrófilos , Animales , Quimiocina CCL2 , Dermatitis Irritante/metabolismo , Inflamación/metabolismo , Interleucina-1beta , Irritantes/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neutrófilos/metabolismo , Receptores CCR2/genética , Receptores CCR2/metabolismo , Receptores de Quimiocina/metabolismo , Piel/metabolismo , TensoactivosRESUMEN
Basophils have been implicated in type 2 inflammation and numerous disorders in the skin such as helminth infection, atopic dermatitis, and urticaria. Although similar in form and function to tissue-resident mast cells, classical studies on basophils have centered on those from the hematopoietic compartment. However, increasing studies in tissues like the skin demonstrate that basophils may take on particular characteristics by responding to unique developmental, chemotactic, and activation cues. Herein, we highlight how recent studies in barrier immunology suggest the presence of skin-homing basophils that harbor a unique identity in terms of phenotype, function, and motility. These concepts may uniquely inform how basophils contribute to diseases at multiple epithelial surfaces and our ability to therapeutically target the innate immune system in disease.
Asunto(s)
Dermatitis Atópica , Urticaria , Humanos , Basófilos , Piel , InflamaciónRESUMEN
Inflammatory skin diseases including atopic dermatitis (AD) and psoriasis (PSO) are underpinned by dendritic cell (DC)-mediated T cell responses. Currently, the heterogeneous human cutaneous DC population is incompletely characterized, and its contribution to these diseases remains unclear. Here, we performed index-sorted single-cell flow cytometry and RNA sequencing of lesional and nonlesional AD and PSO skin to identify macrophages and all DC subsets, including the newly described mature LAMP3+BIRC3+ DCs enriched in immunoregulatory molecules (mregDC) and CD14+ DC3. By integrating our indexed data with published skin datasets, we generated a myeloid cell universe of DC and macrophage subsets in healthy and diseased skin. Importantly, we found that CD14+ DC3s increased in PSO lesional skin and co-produced IL1B and IL23A, which are pathological in PSO. Our study comprehensively describes the molecular characteristics of macrophages and DC subsets in AD and PSO at single-cell resolution, and identifies CD14+ DC3s as potential promoters of inflammation in PSO.
Asunto(s)
Dermatitis Atópica/patología , Interleucina-1beta/metabolismo , Subunidad p19 de la Interleucina-23/metabolismo , Células de Langerhans/patología , Psoriasis/patología , Dermatitis Atópica/metabolismo , Expresión Génica , Redes Reguladoras de Genes , Humanos , Interleucina-15/metabolismo , Células de Langerhans/metabolismo , Receptores de Lipopolisacáridos/metabolismo , Macrófagos/citología , Psoriasis/metabolismo , Análisis de la Célula IndividualRESUMEN
BACKGROUND: Percutaneous sensitization is associated with various allergic diseases, including asthma and food allergies. However, the immunologic mechanisms underlying how the skin regulates percutaneous sensitization are still unclear. OBJECTIVE: We aimed to investigate whether and how CD4+Foxp3+ regulatory T (Treg) cells residing in the skin regulate percutaneous sensitization in the skin. METHODS: Selective reduction of numbers of cutaneous Treg cells was achieved by means of intradermal injection of diphtheria toxin into the ear skin of Foxp3DTR mice, in which Treg cells specifically express the diphtheria toxin receptor fused with green fluorescent protein. RESULTS: Thirty percent to 40% of cutaneous Treg cells were capable of IL-10 production in both mice and human subjects. Selective reduction of cutaneous Treg cells at the sensitization site promoted migration of antigen-bearing dendritic cells (DCs) to the draining lymph nodes (dLNs). Accordingly, sensitization through the skin with reduced numbers of Treg cells led to enhanced antigen-specific immune responses in the dLNs, including both effector T-cell differentiation and T cell-dependent B-cell responses, such as the development of germinal center B cells expressing IgG1 and IgE. Furthermore, antigen-bearing cutaneous DC migration was enhanced in mice with IL-10 deficiency restricted to the cutaneous Treg cell compartment, suggesting an important role of cutaneous IL-10+ Treg cells in limiting percutaneous sensitization. Treg cells with a skin-homing phenotype in skin dLNs expressed high levels of IL-10, suggesting that they contribute to renewal and maintenance of the cutaneous IL-10+ Treg cell population. CONCLUSION: Skin-resident Treg cells limit percutaneous sensitization by suppressing antigen-bearing DC migration through in situ IL-10 production.
Asunto(s)
Linfocitos B/inmunología , Células Dendríticas/inmunología , Interleucina-10/metabolismo , Piel/inmunología , Linfocitos T Reguladores/inmunología , Administración Cutánea , Animales , Presentación de Antígeno , Movimiento Celular , Células Cultivadas , Factores de Transcripción Forkhead/metabolismo , Humanos , Inmunización , Inmunoglobulina E/metabolismo , Interleucina-10/genética , Activación de Linfocitos , Ratones , Ratones Noqueados , Ratones TransgénicosAsunto(s)
Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Neoplasias Cardíacas/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Micosis Fungoide/inmunología , Neoplasias Cutáneas/inmunología , Adulto , Antineoplásicos/uso terapéutico , Biomarcadores de Tumor/análisis , Biopsia , Trasplante de Células Madre de Sangre del Cordón Umbilical , Neoplasias Cardíacas/secundario , Neoplasias Cardíacas/terapia , Humanos , Inmunohistoquímica , Inmunofenotipificación , Metástasis Linfática , Masculino , Micosis Fungoide/sangre , Micosis Fungoide/patología , Micosis Fungoide/terapia , Estadificación de Neoplasias , Fenotipo , Neoplasias Cutáneas/sangre , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/terapiaRESUMEN
Reticulohistiocytoma (RH) is a dermal histiocytic infiltration composed of large histiocytes with eosinophilic glassy cytoplasm. RH is classified into three clinical forms: solitary RH, diffuse cutaneous RH without systemic involvement and multicentric reticulohistiocytosis with systemic diseases. Solitary RH generally manifests as a nodular lesion in adults without accompanying systemic diseases. Herein, we describe a case of solitary RH with an atypical clinical manifestation as a red-brown-colored plaque in a 2-year-old boy. Atypical presentations of RH may pose diagnostic difficulty unless RH is considered. A correct diagnosis of RH can ensure avoidance of unnecessary invasive procedures.
Asunto(s)
Síndrome de Hipersensibilidad a Medicamentos/etiología , Isoxazoles/efectos adversos , Eosinofilia Pulmonar/inducido químicamente , Corticoesteroides/administración & dosificación , Biopsia , Síndrome de Hipersensibilidad a Medicamentos/diagnóstico , Síndrome de Hipersensibilidad a Medicamentos/tratamiento farmacológico , Femenino , Humanos , Persona de Mediana Edad , Prednisolona/administración & dosificación , Eosinofilia Pulmonar/diagnóstico , Eosinofilia Pulmonar/tratamiento farmacológico , Tomografía Computarizada por Rayos X , Resultado del Tratamiento , ZonisamidaRESUMEN
Pencil core granuloma is characterized by a delayed foreign-body reaction against retained fragments of pencil lead. Previous case reports presented pencil core granuloma resembling malignant melanoma, haemangioma, or soft tissue sarcoma. We present a case of pencil core granuloma arising from the palm 25 years after the initial injury. The patient presented a bluish nodule that had been present over 25 years before. The nodule initially measured 5 mm in diameter. However, five years before presentation, it suddenly enlarged to the size of 30 mm during six months. Computed tomography (CT) of the lesion revealed a linear radiopaque structure of 8 mm long with a mass on its distal end. Surgical resection revealed a bluish muddy mass and pencil lead. Histological examination revealed degenerative tissue with calcification surrounded by massive amounts of black granular material in the middle and lower dermis.