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.

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.

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

Aspergillus fumigatus-Stimulated Human Corneal Epithelial Cells Induce Pyroptosis of THP-1 Macrophages by Secreting TSLP.

Fungal keratitis (FK) is a keratopathy caused by pathogenic fungal infection. The aim of this work is to explore the role of thymic stromal lymphopoietin (TSLP) in FK. Human corneal epithelial cells (HCECs) were treated with Aspergillus fumigatus hyphae, and we found that TSLP was highly expressed and secreted in the hyphae-treated HCECs. Hyphae-treated HCECs or TSLP treatment enhanced the expression of caspase-1 P20, GSDMD-N (p30), IL-1β, and IL-18 in the human THP-1 macrophages. The influence conferred by hyphae-treated HCECs or TSLP treatment was rescued by TSLP neutralizing antibody or VX-765 (caspase-1 inhibitor) treatment. Moreover, TSLP treatment promoted the expression of NLRP3, ASC, caspase-1 P20, GSDMD-N (p30), IL-1β, and IL-18 in the THP-1 macrophages, which was abolished by NLRP3 knockdown. Furthermore, TSLPR silencing suppressed the expression of NLRP3, ASC, caspase-1 P20, GSDMD-N (p30), IL-1β, and IL-18 in the TSLP-treated THP-1 macrophages. In conclusion, our article confirms that Aspergillus fumigatus-stimulated HCECs induce pyroptosis of THP-1 macrophages by secreting TSLP. TSLP/TSLPR induces caspase-1-dependent pyroptosis through activation of NLRP3 inflammasome. Thus, our work suggests that TSLP may be a potential target for FK treatment.

Interleukin 25, thymic stromal lymphopoietin and house dust mites in pathogenesis of atopic dermatitis.

Atopic dermatitis (AD) is the most common chronic inflammatory skin disease in the world. It is characterized by recurrent eczematous skin lesions, fluctuating course and chronic pruritus. Increasing evidence suggest that AD is more common in adults than previously thought. The disease is characterized by an impaired skin barrier, aberrant Th2-type cytokine production and intensive pruritus. Epithelial keratinocytes constitute the first physical, chemical and immunological barrier, classified as a part of the innate defense system. These keratinocytes secrete various factors, e.g. alarmins such as thymic stromal lymphopoietin (TSLP) and interleukin 25 (IL-25). Serum levels of substance P (SP) have been reported to be increased in patients with AD and correlated with itch intensity. Several previous studies reported a positive association between AD severity and house dust mites (HDM) sensitization. The aim of the study was to analyze IL-25, TSLP and SP concentrations in blood serum of adult patients with severe AD, depending on the degree of allergy to HDM. There were 31 adult AD patients enrolled into the study and a control group that consisted of 20 healthy subjects. AD was diagnosed on the basis of Hanifin and Rajka criteria. SCORing Atopic Dermatitis (SCORAD) and visual analogue (VAS) scores were used to assess the intensity of pruritus and blood content of specific IgE to HDM, as well as TSLP, IL-25 cytokines and SP was measured. Our study presents the evidence that IL-25 serum concentration is increased in patients with atopic dermatitis and this cytokine plays an important role in pathogenesis of this disease. HDM could stimulate the release of IL-25 which aggravates the disease severity. Our results corroborate previous findings on the role of TSLP in atopic dermatitis.

The role of Thymic Stromal Lymphopoietin (TSLP) in protection from Type II diabetes

Abstract Within the past 30 years, obesity and associated disorders such as Type II diabetes are rapidly becoming world-wide epidemics. Type II diabetes, caused by the loss of insulin sensitivity, accounts for $327 billion annually in the U.S. Recent studies have shown that the immune system plays a critical role in regulating the metabolic function of adipose tissue. Importantly, Type II diabetes is a disease of chronic low-grade inflammation, and adipose T regulatory cells (Tregs) can help maintain insulin sensitivity by suppressing the inflammation caused by monocytes, CD8 T, and Natural Killer (NK) cells. We have previously reported that topical application of the Vitamin D3 analog MC903 induces a two-fold increase in the proportion and absolute number of Tregs systemically. MC903 induces production of the cytokine Thymic Stromal Lymphopoietin (TSLP) from skin keratinocytes, and TSLP stimulates proliferation of Tregs through activation of dendritic cells. In a model of diet-induced Type II diabetes, we found that mice on high fat diet treated with MC903 compared to vehicle demonstrate improved metabolic parameters, including increased glucose tolerance and decreased insulin resistance, decreased fasting glucose and insulin, and lower liver triglycerides. Concordantly, treatment of mice with a TSLP-expressing adeno-associated virus also induced similar results, suggesting that TSLP is sufficient to improve insulin sensitivity. Importantly, there was a robust increase in Tregs and decrease in CD8 T cells and NK cells in the adipose of MC903 and TSLP-treated mice. Together, our results suggest that activation of TSLP signaling may be a therapeutic immunotarget for improving insulin sensitivity and preventing Type II diabetes.