Ursolic acid (UA), a pentacyclic triterpene, exhibits diverse pharmacological effects, including potential treatment for allergic diseases. It downregulates thymic stromal lymphopoietin (TSLP) and disrupts mast cell signaling pathways. However, the exact molecular mechanism by which UA interferes with mast cell action remains unclear. Therefore, the current study aimed to uncover molecular entities underlying the effect of UA on mast cells and its potential antipruritic effect, specifically investigating its modulation of key molecules such as TRPV4, PAR2, and MRGPRX2, which are involved in TSLP regulation and sensation. Calcium imaging experiments revealed that UA pretreatment significantly suppressed MRGPRX2 activation (and its mouse orthologue MrgprB2), a G protein-coupled receptor predominantly expressed in mast cells. Molecular docking predictions suggested potential interactions between UA and MRGPRX2/MrgprB2. UA pretreatment also reduced mast cell degranulation through MRGPRX2 and MrgprB2-dependent mechanisms. In a dry skin mouse model, UA administration decreased tryptase and TSLP production in the skin, and diminished TSLP response in the sensory neurons. While PAR2 and TRPV4 activation enhances TSLP production, UA did not inhibit their activity. Notably, UA attenuated compound 48/80-induced scratching behaviors in mice and suppressed spontaneous scratching in a dry skin model. The present study confirms the effective inhibition of UA on MRGPRX2/MrgprB2, leading to reduced mast cell degranulation and suppressed scratching behaviors. These findings highlight the potential of UA as an antipruritic agent for managing various allergy- or itch-related conditions.

CONCLUSIONS: The Global Initiative for Asthma recommends gradually stepping down treatments to the lowest oral/inhaled corticosteroid doses that control symptoms and exacerbations. Tezepelumab treatment enabled reductions in oral/inhaled corticosteroid doses versus placebo, while preserving asthma symptom control and lung function.

Pancreatic cancer is a very aggressive disease with a dismal prognosis. The tumor microenvironment exerts immunosuppressive activities through the secretion of several cytokines, including interleukin (IL)-1. The IL-1/IL-1 receptor (IL-1R) axis is a key regulator in tumor-promoting T helper (Th)2- and Th17-type inflammation. Th2 cells are differentiated by dendritic cells endowed with Th2-polarizing capability by the thymic stromal lymphopoietin (TSLP) that is secreted by IL-1-activated cancer-associated fibroblasts (CAFs). Th17 cells are differentiated in the presence of IL-1 and other IL-1-regulated cytokines. In pancreatic cancer, the use of a recombinant IL-1R antagonist (IL1RA, anakinra, ANK) in in vitro and in vivo models has shown efficacy in targeting the IL-1/IL-1R pathway. In this study, we have developed sphingomyelin nanosystems (SNs) loaded with ANK (ANK-SNs) to compare their ability to inhibit Th2- and Th17-type inflammation with that of the free drug in vitro. We found that ANK-SNs inhibited TSLP and other pro-tumor cytokines released by CAFs at levels similar to ANK. Importantly, inhibition of IL-17 secretion by Th17 cells, but not of interferon-γ, was significantly higher, and at lower concentrations, with ANK-SNs compared to ANK. Collectively, the use of ANK-SNs might be beneficial in reducing the effective dose of the drug and its toxic effects.

UNASSIGNED: This study entails an association between bronchial asthma and common single nucleotide polymorphisms (SNPs) in thymic stromal lymphopoietin (TSLP) gene; rs2289278, rs3806933, rs2289276, and rs1837253.
UNASSIGNED: The databases of PubMed, Embase, Web of Science, and Google Scholar were searched for studies reporting TSLP polymorphisms and asthma from inception to January 2022. Hardy-Weinberg equilibriums (HWE) for each polymorphism of the control group were checked using the χ 2 test. The association was estimated by means of odds ratio (OR) with 95% CI in both dominant and recessive modes of inheritance, respectively.
UNASSIGNED: Altogether, 11 studies with 3121 asthma cases and 3041 healthy controls were added. Results from six studies showed that the SNP rs2289278 had a protective role in asthma development (OR=0.65, 95% CI: 0.44-0.97, P=0.04). Pooling of four studies showed that the SNP rs3806933 had higher odds of developing asthma (OR=1.32, 95% CI:1.14-1.54, P<0.01). However, the SNP rs2289276 and rs1837253 showed no significant association. From the subgroup analysis, SNPs rs2289278 and rs1837253 were protective against the development of asthma in Asia. However, SNP rs2289276 showed a risk association in Asia and in adults.
UNASSIGNED: This meta-analysis shows that the SNP rs2289278 has a protective effect on the development of asthma; whereas rs3806933 has a risk of asthma. Additionally, this study adds genomic-based support to the recent FDA approval of tezepelumab, an anti-TSLP agent.

Specific molecular and inflammatory endotypes have been identified for chronic respiratory disorders, including asthma and COPD (chronic obstructive pulmonary disease). These endotypes correspond with clinical aspects of disease, enabling targeted medicines to address certain pathophysiologic pathways, often referred to as \"precision medicine\". With respect to bronchiectasis, many comorbidities and underlying causes have been identified. Inflammatory endotypes have also been widely studied and reported. Additionally, several genes have been shown to affect disease progression. However, the lack of a clear classification has also hampered our understanding of the disease\'s natural course. The aim of this review is, thus, to summarize the current knowledge on biomarkers and actionable targets of this complex pathologic condition and to point out unmet needs, which are required in the design of effective diagnostic and therapeutic trials.

BACKGROUND: 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.

Background: The secretion of alarmin cytokines by epithelial cells, including thymic stromal lymphopoietin (TSLP), interleukin (IL)-25, and IL-33, initiates inflammatory cascades in asthma. However, alarmin cytokine expression in the upper airways in asthma remains largely unknown. Methods: We recruited 40 participants with asthma into four groups as per the Global Initiative for Asthma (GINA) steps (10 in each group of GINA 1/2, 3, 4, and 5). Cells were derived from nasal, buccal, and throat brushings. Intracellular cytokine expression (TSLP, IL-25, and IL-33) was assessed by flow cytometry in cytokeratin 8+ (Ck8+) epithelial cells immediately following collection. Results: TSLP was significantly increased (p < 0.001) in GINA 5 patients across nasal, buccal, and throat Ck8+ epithelial cells, while IL-25 was elevated in nasal and throat samples (p < 0.003), and IL-33 levels were variable, compared with GINA 1-4 patients. Individual GINA subgroup comparison showed that TSLP levels in nasal samples from GINA 5 patients were significantly (p = 0.03) elevated but did not differ between patients with and without nasal comorbidities. IL-25 and IL-33 (obtained from nasal, buccal, and throat samples) were not significantly different in individual groups. Conclusions: Our study demonstrates for the first time that Ck8+ nasal epithelial cells from GINA 5 asthma patients express elevated levels of TSLP.

Conventional immunosuppressants are ineffective for the management of EGPA-related asthma. Tezepelumab is a human monoclonal antibody that inhibits thymic stromal lymphopoietin (TLSP) that has proven efficacy in several phase 3 studies for the treatment of asthma. We treated with off-label tezepelumab the first two patients with severe refractory EPGA-related asthma. These preliminary findings suggest that targeting upstream signaling of the T2 inflammatory pathway can improve symptoms, reduce BVAS and increase Asthma Control Test scores, even in patients with refractory asthma who have failed several previous lines of treatment. Nevertheless, by analogy with dupilumab-induced IL-4/13 blockade, the persistence of sputum eosinophilia (reported in both patients) raises questions as to whether TSLP inhibition could lead to a rebound of eosinophilia and potentially to eosinophil-related symptoms in patients with EGPA.

Systemic sclerosis (SSc) is a complex autoimmune connective-tissue disease, characterised by vasculopathy and fibrosis of the skin and internal organs. Activation of microvascular endothelial cells (ECs) causes the intimal hyperplasia that characterises the vascular remodelling in SSc. The most frequent complication of SSc is the development of digital ulcers (DUs). Thymic stromal lymphopoietin (TSLP) may trigger fibrosis and sustain vascular damage. Aim of this study was to evaluate the correlation between serum level of TSLP and DUs.
75 consecutive SSc patients were enrolled and serum TSLP levels were measured. The presence of history of DUs (HDU) was evaluated. Recurrent new DUs were defined as the presence of at least 3 episodes of DUs in a 12-months follow up period. The risk of developing new DUs was calculated by applying the capillaroscopic skin ulcer risk index (CSURI).
The median value of TSLP was higher in patients with HDU than patients without HDU [181.67 pg/ml (IQR 144.67; 265.66) vs 154.67 pg/ml (IQR 110.67; 171.33), p < 0.01]. The median value of TSLP was higher in patients with an increased CSURI index than patients without an increased CSURI [188 pg/ml (IQR 171.33; 246.33) vs 159.33 pg/ml (IQR 128.67; 218), p < 0.01]. Kaplan-Meier curves demonstrated that free survival from new DUs was significantly (p < 0.01) lower in SSc patients with increased TSLP serum levels.
TSLP might have a key role in digital microvascular damage of SSc patients.

BACKGROUND: 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.
METHODS: A comprehensive search of PubMed and Web of Science was conducted to gather information on anti-TSLP antibody and anti-IgE antibody.
RESULTS: 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.
CONCLUSIONS: 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.