Role Of Thymic Stromal Lymphopoietin Research Articles

Role of Thymic Stromal Lymphopoietin in the Pathophysiology of Asthma and Clinical and Biological Effects of Blockade With Tezepelumab.

The airway epithelium is the first line of defense of the respiratory system against the external environment. It plays an active role in the initiation of immune and allergic responses against potential hazards. Among the various specialized cells and cytokines that participate in epithelium-induced responses, alarmins are particularly interesting, given their ample role in mediating T2 and non-T2 inflammatory mechanisms involved in the pathogenesis of asthma. Thymic stromal lymphopoietin (TSLP) is an alarmin with broad effects in asthma that result from its widespread action on multiple cell types, including eosinophils, mast cells, dendritic cells, and group-2 innate lymphoid cells. Its role in allergy-mediated responses, eosinophilic inflammation, airway hyperresponsiveness, mucus hyperproduction, viral tolerance, and airway remodeling is of the utmost importance, as more comprehensive asthma assessments have been developed to explore these pathogenic features. Therefore, blockade with targeting molecules, such as monoclonal antibodies, has emerged as a promising therapeutic option, particularly in patients with multiple pathogenic pathways. In this review, we examine the roles of alarmins (mainly TSLP) in the pathogenesis of asthma and clinical expression and discuss the effects of inhibiting TSLP on several inflammatory and clinical outcomes. We also review the literature supporting treatment with anti-TSLP biologics and the unanswered questions and unmet needs associated with targeting alarmins in asthma.

Local receptor-interacting protein kinase 2 inhibition mitigates house dust mite-induced asthma.

House dust mite is the most frequent trigger of allergic asthma, with innate and adaptive immune mechanisms playing critical roles in outcomes. We recently identified the nucleotide-binding oligomerisation domain 1 (NOD1)/receptor-interacting serine/threonine protein kinase 2 (RIPK2) signalling pathway as a relevant contributor to murine house dust mite-induced asthma. This study aimed to evaluate the effectiveness of a pharmacological RIPK2 inhibitor administered locally as a preventive and therapeutic approach using a house dust mite-induced asthma model in wild-type and humanised NOD1 mice harbouring an asthma-associated risk allele, and its relevance using air-liquid interface epithelial cultures from asthma patients. A RIPK2 inhibitor was administered intranasally either preventively or therapeutically in a murine house dust mite-induced asthma model. Airway hyperresponsiveness, bronchoalveolar lavage composition, cytokine/chemokine expression and mucus production were evaluated, as well as the effect of the inhibitor on precision-cut lung slices. Furthermore, the inhibitor was tested on air-liquid interface epithelial cultures from asthma patients and controls. While local preventive administration of the RIPK2 inhibitor reduced airway hyperresponsiveness, eosinophilia, mucus production, T-helper type 2 cytokines and interleukin 33 (IL-33) in wild-type mice, its therapeutic administration failed to reduce the above parameters, except IL-33. By contrast, therapeutic RIPK2 inhibition mitigated all asthma features in humanised NOD1 mice. Results in precision-cut lung slices emphasised an early role of thymic stromal lymphopoietin and IL-33 in the NOD1-dependent response to house dust mite, and a late effect of NOD1 signalling on IL-13 effector response. RIPK2 inhibitor downregulated thymic stromal lymphopoietin and chemokines in house dust mite-stimulated epithelial cultures from asthma patients. These data support that local interference of the NOD1 signalling pathway through RIPK2 inhibition may represent a new therapeutic approach in house dust mite-induced asthma.

Exploring the therapeutic potential of monoclonal antibodies targeting TSLP and IgE in asthma management.

In recent years, there has been a growing interest in the utilization of biologic therapies for the management of asthma. Both TSLP and IgE are important immune molecules in the development of asthma, and they are involved in the occurrence and regulation of inflammatory response. A comprehensive search of PubMed and Web of Science was conducted to gather information on anti-TSLP antibody and anti-IgE antibody. This investigation elucidates the distinct mechanistic roles of Thymic Stromal Lymphopoietin (TSLP) and Immunoglobulin E (IgE) in the pathogenesis of asthma, with a particular emphasis on delineating the therapeutic mechanisms and pharmacological properties of monoclonal antibodies targeting IgE and TSLP. Through a meticulous examination of clinical trials involving paradigmatic agents such as omalizumab and tezepelumab, we offer valuable insights into the potential treatment modalities for diseases with shared immunopathogenic pathways involving IgE and TSLP. The overarching objective of this comprehensive study is to delve into the latest advancements in asthma therapeutics and to provide guidance for future investigations in this domain.

The role of thymic stromal lymphopoietin in cutaneous disorders.

Thymic Stromal Lymphopoietin (TSLP) is an important cytokine that invokes early immune responses. TSLP, an IL-7-like cytokine encoded by the TSLP gene, activates JAK1 and JAK2 signaling pathways, stimulating dendritic cells to induce inflammatory Th2 cells. This cytokine is associated with pruritus in various cutaneous disorders, particularly atopic dermatitis. Varying levels of the cytokine TSLP have been demonstrated in studies of different cutaneous disorders. Pharmacological treatment targeting TSLP has been explored recently, particularly in the realm of atopic dermatitis.This review explores the relation of TSLP to cutaneous diseases, highlighting its potential as a biomarker for monitoring disease progression in discoid lupus erythematosus (DLE). The pharmacological therapy involving TSLP is discussed, along with the potential role of TSLP promotion in the treatment of alopecia areata. This overview examines the background, structure, and functions of TSLP, with a focus on its association with cutaneous disorders and a special focus on the impact of the atopic march.

TSLP enhances progestin response in endometrial cancer via androgen receptor signal pathway.

The enriched proteins within in vitro fertilisation (IVF)-generated human embryonic microenvironment could reverse progestin resistance in endometrial cancer (EC). The expression of thymic stromal lymphopoietin (TSLP) in EC was evaluated by immunoblot and IHC analysis. Transcriptome sequencing screened out the downstream pathway regulated by TSLP. The role of TSLP, androgen receptor (AR) and KANK1 in regulating the sensitivity of EC to progestin was verified through a series of in vitro and in vivo experiments. TSLP facilitates the formation of a BMP4/BMP7 heterodimer, resulting in activation of Smad5, augmenting AR signalling. AR in turn sensitises EC cells to progestin via KANK1. Downregulation of TSLP, loss of AR and KANK1 in EC patients are associated with tumour malignant progress. Moreover, exogenous TSLP could rescue the anti-tumour effect of progestin on mouse in vivo xenograft tumour. Our findings suggest that TSLP enhances the sensitivity of EC to progestin through the BMP4/Smad5/AR/KANK1 axis, and provide a link between embryo development and cancer progress, paving the way for the establishment of novel strategy overcoming progestin resistance using embryo original factors.

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According to general estimates, from 3�5 % and up to 10 % of patients with asthma have a severe course of the disease, which often continues to remain uncontrolled, despite the maximum use of inhaled corticosteroids and additional controller drugs. Severe asthma creates a large physical, mental, emotional, social and economic burden for patients and is often associated with multimorbidity. The heterogeneity of asthma drives research aimed at defining asthma phenotypes that ultimately reflect different underlying disease mechanisms, including pathogenetic processes and response to environmental factors. The clinical phenotypes of asthma are closely related to the underlying inflammatory processes in this disease and therefore can be divided into 2 main inflammatory phenotypes determined by the dominant immunological pathways that determine the pathology of bronchial asthma: eosinophilic and non-eosinophilic. Phenotyping patients is important for the differential diagnosis of asthma, risk assessment, treatment selection, and monitoring response to treatment. Accurate identification of the phenotype is particularly important for the selection of a biological drug for the treatment of severe asthma and for predicting the response to treatment with it. But these phenotypes are not fixed and can change over time in response to new environmental triggers (viral infections, inhaled allergens, smoking, air pollution). The main cytokines in the T2 type of inflammation in the airways, which is characteristic of severe asthma, are IL-4, IL-5 and IL- 13, IL-17, but an equally significant role in this process is also played by alarmins (inflammation mediators produced, in particular, cells of the bronchial epithelium), which include IL-33, IL-25 and thymic stromal lymphopoietin (TSLP). Clinical features of asthma associated with TSLP include: 1) degree of severity; 2) risk and frequency of exacerbations; 3) the degree of lung function decline; 4) decrease in the patient's response to glucocorticosteroids; 5) decrease in immune response and susceptibility to acute respiratory viral infections; 6) potential remodulation of the respiratory tract; 7) bronchial hyperreactivity and mucus blockage. Therefore, the role of TSLP in the pathogenesis of severe asthma is very significant, so its therapeutic effect (anti-TSLP therapy using tezepelumab) can be considered a new promising direction of biological therapy for patients with bronchial asthma, especially in its severe form. Key words: bronchial asthma, severe form, type 2 inflammation, biomarkers of inflammation, thymic stromal lymphopoietin, biological therapy, tezepelumab.

Thymic stromal lymphopoietin: evaluating its role as a new marker related to presence of psoriasis vulgaris and its severity

Background Thymic stromal lymphopoietin (TSLP), a proallergic cytokine, and T cell-derived CD40 ligand (CD40L) may collaborate to increase the production of IL-23 in psoriasis patients. One key cytokine, IL-23, is responsible for the unwarranted immune response in psoriasis sufferers. Aim The current study aims to shed light on the possible role of TSLP as a novel biomarker related to presence of psoriasis vulgaris lesions and its severe forms with exclusion of people with atopic dermatitis, allergic rhinitis, rheumatoid arthritis, graft versus host disease (GVHD), blood diseases and patient on anticoagulant therapy as well as pregnant and lactating females. Patients and methods 40 subjects with psoriasis vulgaris participated in the current case-controlled research, whereas 40 healthy volunteers of similar age and gender served as the control group. The degree and extent of the illness were evaluated utilizing the psoriasis area and severity index (PASI) score. Serum was separated after blood samples from the venous blood of the subjects and control participants were taken. As soon as possible, the serum samples were frozen at −20°C. The Sandwich Enzyme-Linked Immunosorbant Assay (ELISA) was utilized to quantify serum TSLP. Results The case group’s serum TSLP levels rose statistically substantially more than those of the control group. In the cases group, there was a statistically strong positive relation between serum TSLP levels and PASI scores (P: < 0.001). There is a statistically strong positive relation between serum TSLP and patients’ age and illness duration, a statistically substantial rise in blood TSLP values in psoriatic arthritis patients and smokers. Conclusion Patients with psoriasis have higher serum TSLP levels, which are proportional to the disease’s severity.

Thymic stromal lymphopoietin participates in the host response to intra-amniotic inflammation leading to preterm labor and birth

The aim of this study was to establish the role of thymic stromal lymphopoietin (TSLP) in the intra-amniotic host response of women with spontaneous preterm labor (sPTL) and birth. Amniotic fluid and chorioamniotic membranes (CAM) were collected from women with sPTL who delivered at term (n = 30) or preterm without intra-amniotic inflammation (n = 34), with sterile intra-amniotic inflammation (SIAI, n = 27), or with intra-amniotic infection (IAI, n = 17). Amnion epithelial cells (AEC), Ureaplasma parvum, and Sneathia spp. were also utilized. The expression of TSLP, TSLPR, and IL-7Rα was evaluated in amniotic fluid or CAM by RT-qPCR and/or immunoassays. AEC co-cultured with Ureaplasma parvum or Sneathia spp. were evaluated for TSLP expression by immunofluorescence and/or RT-qPCR. Our data show that TSLP was elevated in amniotic fluid of women with SIAI or IAI and expressed by the CAM. TSLPR and IL-7Rα had detectable gene and protein expression in the CAM; yet, CRLF2 was specifically elevated with IAI. While TSLP localized to all layers of the CAM and increased with SIAI or IAI, TSLPR and IL-7Rα were minimal and became most apparent with IAI. Co-culture experiments indicated that Ureaplasma parvum and Sneathia spp. differentially upregulated TSLP expression in AEC. Together, these findings indicate that TSLP is a central component of the intra-amniotic host response during sPTL.

The Role of TSLP in Atopic Dermatitis: From Pathogenetic Molecule to Therapeutical Target.

Atopic dermatitis (AD) is a kind of chronic skin disease with inflammatory infiltration, characterized by skin barrier dysfunction, immune response dysregulation, and skin dysbiosis. Thymic stromal lymphopoietin (TSLP) acts as a regulator of immune response, positively associated with AD deterioration. Mainly secreted by keratinocytes, TSLP interacts with multiple immune cells (including dendritic cells, T cells, and mast cells), following induction of Th2-oriented immune response during the pathogenesis of AD. This article primarily focuses on the TSLP biological function, the relationship between TSLP and different cell populations, and the AD treatments targeting TSLP.

TSLP activates the production of IFN-γ via CD8-positive T cells in recurrent tonsillitis

The role of thymic stromal lymphopoietin (TSLP) in chronic infection is not well understood. We report an increased number of cluster of differentiation 8 (CD8+ T) cells and higher expression of TSLP in the tonsil tissues of patients with recurrent tonsillitis as compared to that in the tonsil tissues of patients with tonsillar hypertrophy. Stimulation of tonsil CD8+ T cells with TSLP in the recurrent tonsillitis group resulted in higher production of interferon gamma (IFN-γ) and increased cell proliferation when compared to that in the tonsillar hypertrophy group. These results suggest the possibility that recurrent infection of tonsils may enhance local CD8+ T cell proliferation and IFN-γ and TSLP production. Anti-TSLP antibodies, which are potential therapeutic agents in allergic diseases, could have beneficial effects in patients with recurrent tonsillitis.

Keratinocyte-derived cytokine TSLP promotes growth and metastasis of melanoma by regulating the tumor-associated immune microenvironment.

Malignant melanoma is a major public health issue displaying frequent resistance to targeted therapy and immunotherapy. A major challenge lies in better understanding how melanoma cells evade immune elimination and how tumor growth and metastasis is facilitated by the tumor microenvironment. Here, we show that expression of the cytokine thymic stromal lymphopoietin (TSLP) by epidermal keratinocytes is induced by cutaneous melanoma in both mice and humans. Using genetically engineered models of melanoma and tumor cell grafting combined with TSLP-KO or overexpression, we defined a crosstalk between melanoma cells, keratinocytes, and immune cells in establishing a tumor-promoting microenvironment. Keratinocyte-derived TSLP is induced by signals derived from melanoma cells and subsequently acts via immune cells to promote melanoma progression and metastasis. Furthermore, we show that TSLP signals through TSLP receptor-expressing (TSLPR-expressing) DCs to play an unrecognized role in promoting GATA3+ Tregs expressing a gene signature including ST2, CCR8, ICOS, PD-1, CTLA-4, and OX40 and exhibiting a potent suppressive activity on CD8+ T cell proliferation and IFN-γ production. An analogous population of GATA3-expressing Tregs was also identified in human melanoma tumors. Our study provides insights into the role of TSLP in programming a protumoral immune microenvironment in cutaneous melanoma.

TSLP, IL-33, and IL-25: Not just for allergy and helminth infection

The release of cytokines from epithelial and stromal cells is critical for the initiation and maintenance of tissue immunity. Three such cytokines, thymic stromal lymphopoietin, IL-33, and IL-25, are important regulators of type 2 immune responses triggered by parasitic worms and allergens. In particular, these cytokines activate group 2 innate lymphoid cells, TH2 cells, and myeloid cells, which drive hallmarks of type 2 immunity. However, emerging data indicate that these tissue-associated cytokines are not only involved in canonical type 2 responses but are also important in the context of viral infections, cancer, and even homeostasis. Here, we provide a brief review of the roles of thymic stromal lymphopoietin, IL-33, and IL-25 in diverse immune contexts, while highlighting their relative contributions in tissue-specific responses. We also emphasize a biologically motivated framework for thinking about the integration of multiple immune signals, including the 3 featured in this review.

TSLP protects against sepsis-induced liver injury by inducing autophagy via activation of the PI3K/Akt/STAT3 pathway

BackgroundLiver injury is the main factor in multiple organ failure caused by sepsis. Thymic stromal lymphopoietin (TSLP) is derived from epithelial cells and plays an important role in inflammation, allergies and cancer. The role of TSLP in sepsis-induced liver injury (SILI) is unclear. The purpose of this study was to investigate the effect of TSLP on sepsis-induced liver injury and to clarify the mechanism. MethodsWild-type (WT) mice and TSLPR knockout (TSLPR-/-) mice were subjected to cecal ligation and puncture (CLP) to generate a SILI model. Liver injury was assessed by measuring the levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), histologic liver injury scores, hepatocyte death, and liver inflammatory factors. Signal pathways were explored in vivo to identify possible mechanisms for TSLP in SILI. ResultsThe expression of TSLP and TSLPR increased during SILI. Deletion of TSLPR exacerbated liver injury in terms of serum ALT, AST, histologic liver injury scores, and liver inflammatory factors. Compared with controls, administration of exogenous recombinant mouse TSLP reduced liver injury in WT mice during SILI, but failed to reduce liver injury in TSLPR–/– mice. TSLP induced autophagy in hepatocytes during SILI. Mechanistically, Akt and STAT3 were activated in WT mice during SILI. The opposite results were observed in TSLPR–/– mice. In addition, the protective effects of TSLP in WT mice were blocked by PI3K inhibitor, LY294002, during SILI. ConclusionThese results suggest that TSLP can improve liver injury caused by sepsis and its specific mechanism may be related to inducing autophagy through the PI3K/Akt/STAT3 signaling pathway.

Role of thymic stromal lymphopoietin in allergy and beyond.

Thymic stromal lymphopoietin (TSLP) is a pleiotropic cytokine that acts on multiple cell lineages, including dendritic cells, T cells, B cells, neutrophils, mast cells, eosinophils and innate lymphoid cells, affecting their maturation, survival and recruitment. It is best known for its role in promoting type 2 immune responses such as in allergic diseases and, in 2021, a monoclonal antibody targeting TSLP was approved for the treatment of severe asthma. However, it is now clear that TSLP has many other important roles in a variety of settings. Indeed, several genetic variants for TSLP are linked to disease severity, and chromosomal alterations in TSLP are common in certain cancers, indicating important roles of TSLP in disease. In this Review, we discuss recent advances in TSLP biology, highlighting how it regulates the tissue environment not only in allergic disease but also in infectious diseases, inflammatory diseases and cancer. Encouragingly, therapies targeting the TSLP pathway are being actively pursued for several diseases.

TSLP up-regulates inflammatory responses through induction of autophagy in T cells.

Thymic stromal lymphopoietin (TSLP), a type I cytokine belonging to the IL-2 cytokine family, promotes Th2-mediated inflammatory responses. The aim of this study is to investigate whether TSLP increases inflammatory responses via induction of autophagy using a murine T cell lymphoma cell line, EL4 cells, and lipopolysaccharide (LPS)-injected mice. TSLP increased expression levels of autophagy-related factors, such as Beclin-1, LC3-II, p62, Atg5, and lysosome associated membrane protein 1/2, whereas these factors increased by TSLP disappeared by neutralization of TSLP in EL4 cells. TSLP activated JAK1/JAK2/STAT5/JNK/PI3K, while the blockade of JAK1/JAK2/STAT5/JNK/PI3K signaling pathways reduced the expression levels of Beclin-1, LC3-II, and p62 in TSLP-stimulated EL4 cells. In addition, TSLP simultaneously increased levels of inflammatory cytokines via induction of autophagy by activation of JAK1/JAK2/STAT5/JNK/PI3K signaling pathways. In an LPS-induced acute liver injury (ALI) mouse model, exogenous TSLP increased expression levels of Beclin-1 and LC3-II, whereas functional deficiency of TSLP by TSLP siRNA resulted in lower expression of Beclin-1, LC3-II, and inflammatory cytokines, impairing their ability to form autophagosomes in ALI mice. Thus, our findings show a new role of TSLP between autophagy and inflammatory responses. In conclusion, regulating TSLP-induced autophagy may be a potential therapeutic strategy for inflammatory responses.

The role of thymic stromal lymphopoietin in the development of chronic otitis media with effusion.

To investigate the effect of thymic stromal lymphopoietin on the development of chronic otitis media with effusion MATERIALS AND METHODS: This study was conducted on 40 patients who had adenoidectomy operation. The objects were divided into two groups. Group 1; adenoidectomy with chronic serous otitis media, group 2; adenoidectomy without chronic serous otitis media. Serum and tissue thymic stromal lymphopoietin levels were measured by ELISA. Serum and tissue TLSP levels, mast cell count, adenoid size were compared between the groups. Twenty-four (60%) of patients were female and 16 (40%) were male. Twenty patients (55%) had adenoid hypertrophy with chronic serous otitis media, and 18 (45%) had adenoid hypertrophy without chronic serous otitis media. The mean age of the patients was 6.21 ± 2.31years. The mean mast cell count was significantly higher in group 1 compared with group 2 (p = 0.017). The mean tissue thymic stromal lymphopoietin measurement was also significantly higher in group 1 than group 2 (p = 0.023). However, there was no significant difference in regards to serum levels between the groups (p = 0.480). The number of mast cells as well as thymic stromal lymphopoietin levels in the adenoids of children was significantly high in the chronic serous otitis media patients. The release of thymic stromal lymphopoietin from the adenoid tissue plays a role in initiating and maintaining a local inflammatory reaction in the eustachian tube that may lead eventually to middle ear effusion in non-atopic patients.

The role of thymic stromal lymphopoietin (TSLP) in asthma

The role of thymic stromal lymphopoietin (TSLP) in asthma

TSLP Induces Platelet Mitophagy and Promotes Thrombosis in Kawasaki Disease

Background: Kawasaki disease (KD) is an acute systemic vasculitis primarily affecting infants and children with an unclear etiology. Coronary artery aneurysm (CAA) is a common manifestation in severe KD patents, which may lead to thrombotic cardiovascular events such as heart attack and stroke even years after onset. Although platelet activation is common in KD patients, but the underlying cause of platelet activation and thrombosis remains unclear. The present study is to investigate the role of thymic stromal lymphopoietin (TSLP) in KD-associated thrombosis. Methods: We included 129 healthy controls and 310 KD patients. And conducted a protein chip assay and discovered a significant upregulation in thymus stromal lymphopoietin (TSLP), especially those with thrombosis KD patients, and TSLP induces platelet activation, mitophagy, and thrombosis in vitro. Clinical samples (plasma and platelets) from KD patients and healthy control were analyzed via ELISA, immunofluorescent confocal microscopy, flow cytometry, western blot, immunoprecipitation and thrombosis assays. Findings: To discover potential proteins underlying platelet activation in KD, we conducted a protein chip assay using clinical samples and discovered a significant upregulation in thymus stromal lymphopoietin (TSLP), a novel interleukin-7 (IL-7)-like cytokine that promotes pathological inflammation and most notably, platelet activation. The upregulation of TSLP in KD patients was corroborated by ELISA, which showed a further increase of TSLP in convalescent patients complicated with thrombosis. The expression of TSLP receptors (TSLPRs) on platelets were also significantly upregulated in KD patients complicated with thrombosis. Platelet activation, apoptosis, and mitochondrial autophagy (mitophagy) were increased in KD patients, which were exacerbated in patients complicated with thrombosis. In vitro, TSLP induced platelet activation and platelet mitophagy as we observed in KD patients, as well as thrombosis, which was attenuated by the mitophagy inhibitor Mvidi and comparable to mitophagy agonist CCCP. Co-immunoprecipitation in TSLP-treated platelets revealed TSLPR bound to mitophagy regulators, Parkin and VDAC1, suggesting a potential novel TSLP-mediated platelet mitophagy pathway. Interpretation: Our results demonstrate that TSLP induces platelet mitophagy via a novel TSLPR/Parkin/VDAC1 mitophagy pathway that promotes thrombosis in KD. To the best of our knowledge, this is the first report that shows TSLP plays an important role in KD patients complicated with thrombosis. These results suggest TSLP as a novel anti-thrombotic therapeutic target for KD-associated thrombosis. Funding: Canadian Institutes of Health Research Foundation grant, the Guangdong Natural Science Foundation grant, the Guangzhou Science and Technology Program Project grant, the Guangzhou Institute of Pediatrics/Guangzhou Women and Children's Medical Center Foundation grant. Declaration of Interest: The authors report no conflicts of interest. Ethical Approval: This study was approved by the Ethics Committee of Guangzhou Women and Children's Medical Center (Number: 2014073009 and 2018052105).

TSLP Produced by Aspergillus fumigatus-Stimulated DCs Promotes a Th17 Response Through the JAK/STAT Signaling Pathway in Fungal Keratitis.

PurposeThe purpose of this study was to explore the role of thymic stromal lymphopoietin (TSLP) secreted by Aspergillus fumigatus–stimulated dendritic cells (DCs) during the T helper 17 (Th17) immune response, and further clarify the mechanisms contributing to the Th17 immune response of fungal keratitis (FK).MethodsA carboxyfluorescein diacetate succinimidyl ester assay, PCR, and flow cytometry were performed to detect Th17 differentiation of CD4+ T cells; PCR, ELISA, and Western blot were used to detect the expression of TSLP and JAK/STAT–related proteins; Signaling pathways involved in Th17 response was evaluated using RNA sequence; C57BL/6 mice were infected with A. fumigatus and treated with ruxolitinib or BBI608. Slit-lamp examination, fluorescein staining, and clinical scores were used to assess the clinical manifestation.ResultsA. fumigatus–infected DCs could drive naïve CD4+ T-cell proliferation and promote the production of Th17 cytokines IL-17A, IL-17F, and IL-22. A. fumigatus stimulation increased the expression of TSLP in DCs. DC-derived TSLP contributed to a Th17-type inflammatory response via the JAK/STAT signaling pathway. TSLP small interfering RNA, TSLPR small interfering RNA, or JAK/STAT inhibitors inhibited the Th17 immune response induced by A. fumigatus–infected DCs. Moreover, TSLP promoted A. fumigatus keratitis disease progression in a mouse model. However, inhibition of the JAK/STAT signaling pathway using a specific inhibitor reversed the development of FK by A. fumigatus infection.ConclusionsTSLP secreted by A. fumigatus–stimulated DCs played a significant role in the Th17-dominant immune response of FK through its JAK/STAT activation. Our findings may contribute to the elucidation of the molecular mechanisms of FK and to the development of novel therapeutic approaches.

胸腺基质淋巴细胞生成素在不同皮肤病中的作用机制研究

胸腺基质淋巴细胞生成素在不同皮肤病中的作用机制研究