Thymic Stromal Lymphopoietin Research Articles

058 Thymic stromal lymphopoietin instructs dendritic cells to promote IL-31-expressing CD4+ effector memory T cells supporting the itch-scratch-inflammation cycle

058 Thymic stromal lymphopoietin instructs dendritic cells to promote IL-31-expressing CD4+ effector memory T cells supporting the itch-scratch-inflammation cycle

House dust mites stimulate thymic stromal lymphopoietin production in human bronchial epithelial cells and promote airway remodeling through activation of PAR2 and ERK signaling pathway.

House dust mites (HDM) are common aeroallergens linked to airway inflammation and remodeling in asthma. Protease-activated receptor 2 (PAR2) and thymic stromal lymphopoietin (TSLP) may mediate these immune responses. However, how the epithelium influences fibroblasts toward airway remodeling remains unclear. We hypothesize that HDM stimulates human bronchial epithelial cells (HBECs) to produce TSLP via PAR2 activation, driving fibroblasts toward remodeling processes. HBECs were treated with HDM, with or without the PAR2 antagonist FSLLRY-NH2 (FSL), and TSLP expression was measured by qPCR and ELISA. Phosphorylation of MAPKs was assessed by western blotting. Human lung fibroblasts (HLFs) were exposed to recombinant TSLP or conditioned medium (CM) from HDM-stimulated HBECs, with or without anti-TSLP antibodies. Fibroblast proliferation and collagen production were assessed as remodeling markers. HDM increased ERK phosphorylation (not p38 or JNK) and TSLP expression at mRNA and protein levels. FSL preincubation significantly reduced ERK phosphorylation and TSLP production: HDM-stimulated CM induced fibroblast proliferation and collagen production, effects suppressed by anti-TSLP or FSL. Direct treatment with recombinant TSLP also promoted fibroblast proliferation and collagen synthesis. These findings suggest that HDM promotes HBEC-to-HLF paracrine interactions via PAR2-ERK-TSLP axis, participating in airway remodeling. PAR2 antagonists may represent potential therapeutic targets for HDM-induced remodeling processes.

Endogenous Glucagon-Like Peptide-1 Receptor and Glucose-Dependent Insulinotropic Polypeptide Receptor Signaling Inhibits Aeroallergen-Induced Innate Airway Inflammation.

Anti-inflammatory effects of incretin signaling through the glucagon-like peptide-1 receptor (GLP-1R) and the glucose-dependent insulinotropic polypeptide receptor (GIPR) in mice have been reported. Therefore, we hypothesized that signaling through the endogenous GLP-1R and the GIPR individually decreases allergic airway inflammation and that the combination of GLP-1R and GIPR signaling together additively inhibits allergen-induced lung and airway inflammation. WT (C57BL/6J), GLP-1R knockout (KO), GIPR KO, and GLP-1R/GIPR double KO (DKO) mice were challenged intranasally with Alternaria alternata extract (Alt-Ext) or vehicle to evaluate the impact of signaling through these receptors on the innate allergen-induced inflammatory response that is primarily driven by group 2 innate lymphoid cells (ILC2). Alt-Ext-induced IL-33 release in the bronchoalveolar lavage fluid (BALF) was not different between the mouse strains, but thymic stromal lymphopoietin (TSLP) was significantly increased in GLP-1R/GIPR DKO mice challenged with Alt-Ext compared to the other strains. Furthermore, Alt-Ext-induced protein expression of IL-5, IL-13, CCL11, and CCL24 in the lung homogenates, the number of eosinophils, lymphocytes, and neutrophils in the BALF, and the number of lung GATA3+ ILC2 were significantly increased in GLP-1R/GIPR DKO mice compared to the other 3 strains. Furthermore, ICAM-1 expression on lung epithelial cells was increased in GLP-1R/GIPR DKO mice challenged with Alt-Ext compared to the other 3 strains. Deficiency of both GLP-1R and GIPR signaling together increased TSLP release, ILC2 activation, and early type 2 innate immune responses to aeroallergen exposure. Combined GLP-1R and GIPR signaling should be explored for the treatment of asthma.

Effect of Tezepelumab on Sino-Nasal Outcome Test (SNOT)-22 Domain and Symptom-Specific Scores in Patients with Severe, Uncontrolled Asthma and a History of Chronic Rhinosinusitis with Nasal Polyps.

Tezepelumab blocks the activity of thymic stromal lymphopoietin, an epithelial cytokine implicated in the pathogenesis of asthma and chronic rhinosinusitis with nasal polyps (CRSwNP). In a previous analysis, tezepelumab improved asthma and rhinosinusitis symptoms compared with placebo in patients with severe, uncontrolled asthma and a history of CRSwNP in the 2years before randomization in the NAVIGATOR study. This post hoc analysis of patients with a CRSwNP diagnosis at any time before randomization in NAVIGATOR enabled domain and symptom-specific analyses of Sino-Nasal Outcome Test (SNOT)-22 outcomes. Patients (aged 12-80years) with severe, uncontrolled asthma were randomized to tezepelumab 210mg or placebo subcutaneously every 4weeks for 52weeks. SNOT-22 total, domain, and item scores were assessed in patients with a history of CRSwNP. Annualized asthma exacerbation rate (primary efficacy outcome), pre-bronchodilator forced expiratory volume in 1s, and Asthma Control Questionnaire-6, Asthma Quality of Life Questionnaire (standardized) for patients 12years and older, and Asthma Symptom Diary scores were also assessed in patients with and without a history of CRSwNP. Of 1059 patients with severe asthma, 165 (15.6%) had a history of CRSwNP. Tezepelumab treatment resulted in sustained improvements versus placebo in SNOT-22 total score throughout the 52-week study period [least-squares mean difference (95% confidence interval) - 11.08 (- 17.80, - 4.35)]. Tezepelumab improved all five SNOT-22 domain scores (sleep, nasal, function, ear/facial, and emotion) and the five SNOT-22 item scores of most clinical interest (decreased sense of smell/taste, nasal blockage, reduced productivity, waking up tired, and cough). Tezepelumab improved asthma-related clinical outcomes in patients with and without a history of CRSwNP. In patients with severe, uncontrolled asthma and a history of CRSwNP, tezepelumab improved rhinosinusitis symptoms across multiple domains, as well as asthma exacerbations, lung function, asthma control, and health-related quality of life. NCT03347279 ( https://classic. gov/ct2/show/NCT03347279 ).

Critical and diverse role of alarmin cytokines in parasitic infections.

Alarmin cytokines including IL-25, IL-33, and thymic stromal lymphopoietin (TSLP) function as danger signals to trigger host immunity in response to tissue injury caused by pathogenic factors such as parasitic infections. Parasitic diseases also provide an excellent context to study their functions and mechanisms. Numerous studies have indicated that alarmin cytokine released by non-immune cells such as epithelial and stromal cells induce the hosts to initiate a type 2 immunity that drives parasite expulsion but also host pathology such as tissue injury and fibrosis. By contrast, alarmin cytokines especially IL-33 derived from immune cells such as dendritic cells may elicit an immuno-suppressive milieu that promotes host tolerance to parasites. Additionally, the role of alarmin cytokines in parasite infections is reported to depend on species of parasites, cellular source of alarmin cytokines, and immune microenvironment, all of which is relevant to the parasitic sites or organs. This narrative review aims to provide information on the crucial and diverse role of alarmin cytokines in parasitic infections involved in different organs including intestine, lung, liver and brain.

Tacrolimus versus hydrocortisone in management of atopic dermatitis in children, a randomized controlled double-blind study: New insights on TARC, CTACK, TSLP, and E-selectin.

Atopic dermatitis (AD) is a type of chronic inflammatory disorder that affects all age groups including children. AD is characterized by elevated inflammatory marker levels. To assess the safety and effectiveness of topical tacrolimus ointment versus topical hydrocortisone cream in the treatment of pediatric AD by comparing the two treatments' ability to reduce serum cytokines. One hundred AD patients who fulfilled the eligibility criteria completed this clinical study. Two groups of 50 AD patients each were selected from Tanta University's Dermatology Department., Group 1 (the hydrocortisone group) was administered topical hydrocortisone cream for a duration of 4 months. For 4 months, Group 2 was administered tacrolimus topically. Serum levels of thymus and activation regulated chemokine (TARC), cutaneous T cell attractant chemokine (CTAC), interleukin-10 (IL-10), interleukin-6 (IL-6), E selectin (E-selectin), and thymic stromal lymphopoietin (TSLP) were measured during an evaluation of the patients by a dermatologist at the beginning and 4 months after the treatment had been started. Children's Dermatology Life Quality Index was used to assess quality of life in these patients. With the exception of E-selectin, IL-6, and IL-10 (p > .05), the tacrolimus group had a significant reduction in TARC, CTACK, TSLP (p < .05) when compared to its baseline and when compared to the hydrocortisone group. Both groups showed a significant improvement in quality of life but no significant changes between groups were observed. In children with AD, tacrolimus reduces inflammatory biomarkers better than hydrocortisone.

Positioning tezepelumab for patients with severe asthma: from evidence to unmet needs.

Several endotypes of severe asthma with predominantly type 2 inflammation can be distinguished by the immune pathways driving the inflammatory processes. However, in the absence of type 2 inflammation, asthma is less clearly defined and is generally associated with poor responses to conventional anti-asthmatic therapies. Studies have shown that disruption of the epithelial barrier triggers inflammatory responses and increases epithelial permeability. A key aspect of this process is that epithelial cells release alarmin cytokines, including interleukin (IL)-25, IL-33, and thymic stromal lymphopoietin (TSLP), in response to allergens and infections. Among these cytokines, TSLP has been identified as a potential therapeutic target for severe asthma, leading to the development of a new biologic, tezepelumab (TZP). By blocking TSLP, TZP may produce wide-ranging effects. Based on positive clinical trial results, TZP appears to offer a promising, safe, and effective treatment approach. This narrative review examines the evidence for treating severe asthma with TZP, analyses clinical trial findings, and provides clinicians with practical insights into identifying patients who may respond best to this novel biologic therapy.

Interconnection of the Gut-Skin Axis in NC/Nga Mouse with Atopic Dermatitis: Effects of the Three Types of Bifidobacterium bifidum CBT-BF3 (Probiotics, Postbiotics, and Cytosine-Phosphate-Guanine Oligodeoxynucleotide) on T Cell Differentiation and Gut Microbiota.

The gut microbiota is an immune system regulator in the gut-skin axis. Dysfunctional interactions between the gut microbiota and the gut immune system can lead to the development of skin diseases such as atopic dermatitis (AD). Probiotics and postbiotics positively affect the balance of the gut microbiota, immune regulation, protection against pathogens, and barrier integrity. This study investigated the effects of probiotic Bifidobacterium bifidum, postbiotic B. bifidum (heat-killed), and cytosine-phosphate-guanine oligodeoxynucleotide (CpG ODN) on the gut microbiota and T cell differentiation in NC/Nga mice induced with AD. 2,4-Dinitrochlorobenzene-induced AD mice had an increased SCORing atopic dermatitis-index and increased mRNA expression levels of Th2 and Th17 cell transcription factors and cytokines, and thymic stromal lymphopoietin (TSLP) cytokine in their mesenteric lymph nodes (mLNs; p<0.05). However, oral administration of the three types of B. bifidum (probiotics, postbiotics, CpG ODN) to AD mice decreased the mRNA expression levels of Th2 and Th17 cell transcription factors and cytokines as well as TSLP cytokine. They increased the mRNA expression levels of regulatory T (Treg) cell transcription factor and cytokine, galectin-9, and filaggrin genes (p<0.05). These effects were more noticeable in the mLNs than in the spleen. In addition, AD mice showed a decrease in Faecalibacterium prausnitzii, Roseburia spp., Leuconostoc citreum, Weissella cibaria, and Weissella koreensis (p<0.05). However, oral administration of the three types of B. bifidum increased Bacteroides spp., Bifidobacterium spp., F. prausnitzii, and Roseburia spp. (p<0.05).

The role of epithelial alarmins and Th2 cytokines in the inflammatory response in allergic rhinitis

Allergic rhinitis (AR) occupies a leading position among the causes of morbidity throughout the world, to date, it has been diagnosed in 400 million people. In the formation and progression of AR, a significant role is assigned to cytokines associated with the second type of immune response, in particular, IL-4, IL-5, IL-9, IL-13, IL-25, IL-33, thymic stromal lymphopoietin (TSLP). This literature review provides information on the influence of the listed mediators on the structural cells of the nasal cavity and blood immune cells (T- and B-lymphocytes, eosinophils, macrophages, dendritic cells), and discusses their association with the manifestation of AR symptoms and the severity of the disease. The results of studies aimed at establishing the level of IL-4, IL-5, IL-9, IL-13, IL-25, IL-33 and TSLP in biological fluids (blood serum, nasal lavage) and their expression in nasal epithelial cells in patients with AR compared to healthy people are assessed.

Co-Stimulation with TWEAK and TGF-β1 Induces Steroid-Insensitive TSLP and CCL5 Production in BEAS-2B Human Bronchial Epithelial Cells.

Steroid-resistant asthma is a common cause of refractory asthma. Type 2 inflammation is the main inflammatory response in asthma, and the mechanism underlying the steroid-resistance of type 2 inflammation has not been completely elucidated. Tumor-necrosis-factor-like apoptosis-inducing factor (TWEAK) and transforming growth factor (TGF)-β1 are involved in epithelial-mesenchymal transition (EMT) and the production of thymic stromal lymphopoietin (TSLP) and C-C motif chemokine ligand 5 (CCL5). We herein hypothesize that the combined exposure to TWEAK and TGF-β1 may result in the development of steroid resistance in bronchial epithelial cells. The bronchial epithelial cell line BEAS-2B was cultured with or without TGF-β1 or TWEAK, in the presence or absence of dexamethasone (DEX). The roles of Smad-independent pathways and MAP kinase phosphatase 1 (MKP-1) were also explored. Co-stimulation of TWEAK and TGF-β1 induced E-cadherin reduction, N-cadherin upregulation, and TSLP and CCL5 production, which were not suppressed by DEX. Inhibition of the nuclear factor kappa beta (NF-κB) and mitogen-activated protein kinase pathways downregulated steroid-unresponsive TSLP and CCL5 production, whereas knockdown of MKP-1 improved steroid-unresponsive TSLP production, induced by co-stimulation with TWEAK and TGF-β1. Therefore, co-stimulation with TWEAK and TGF-β1 can induce the steroid-insensitive production of TSLP and CCL5 in the bronchial epithelium and may contribute to airway inflammation.

Elevated circulating group-2 innate lymphoid cells expressing activation markers and correlated tryptase AB1 levels in active ascariasis.

Ascaris lumbricoides infection is one of the most common soil-transmitted helminthiasis and IgE response to this helminth may increase the risk of asthma, bronchial hyperreactivity and atopy. There is not enough evidence showing the role of group-2 innate lymphoid cells (ILC2) in the pathogenesis of helminth infections in humans. Here, we aimed to investigate and characterize the influence of Ascaris lumbricoides infection on circulating ILCs in endemically exposed subjects. Non-infected (NI; n=16) and Ascaris-infected (AI; n=16) subjects from an endemic area were included. Two consecutive stool samples from each subject were examined by Kato-Katz to define parasite infection. Antibodies to the ABA-1 antigen of Ascaris and Ascaris extract were measured by ELISA. ILC subsets and their activation markers (CD25, CD69, thymic stromal lymphopoietin receptor (TSLPR) were evaluated in its PBMC by flow cytometry. Proximity extension assay (PEA) was performed to explore plasma proteins associated to infection. No significant differences in the relative or absolute frequencies of total ILCs, ILC1, ILC2 and ILC3 cells were observed regarding the infection status. However, within AI group, IgE-sensitized subjects to ABA-1 had higher frequencies and counts of ILC2 (p<0.05). Frequencies of CD25+, CD69+ and TSLPR+ ILC2 were higher in AI compared to the NI (p<0.01). Additionally, egg burden was positively correlated with CD69+ ILC2 frequencies (r=0.67; p=0.005). Tryptase alpha/beta 1 (TPSAB1), GP6 and several plasma proteins associated with cell growth and granulocyte chemotaxis were highly expressed in the AI group (p<0.05). Interestingly, TPSAB1 levels were positively correlated with ILC2 expressing activation markers frequencies, egg burden and IgE levels against Ascaris. Ascaris infection is associated with increased expression of ILC2 activation markers and TPSAB1, which may contribute to the type-2 response.

Lactobacillus rhamnosus RL-H3-005 and Pediococcus acidilactici RP-H3-006 ameliorate atopic dermatitis in offspring mice by modulating the gut microbiota

The increasing incidence of atopic dermatitis (AD) presents a public health issue, and thus there is an urgent need for safe and effective preventive strategies. In this study, a strategy to reduce the risk of AD in offspring by administering probiotics to the mother was explored. Female mice were given Lactobacillus rhamnosus RL-H3-005 (RL) and Pediococcus acidilactici RP-H3-006 (RP) during pregnancy and lactation period, and their inhibition effects on AD symptoms in offspring mice were evaluated. The results showed that supplementation with RL and RP during pregnancy and lactation period altered not only the gut microbiota community but also microbial community in milk in pregnant mice. Further study showed that pups from RL- and RP-treated pregnant mice had mild symptoms of AD, characterized by reduced epidermal thickness in the ear tissues and numbers of mast cells, which was associated with the reduction in secretory immunoglobulin A (sIgA), immunoglobulin E (IgE), IL-4, IL-5, IL-13, thymic stromal lymphopoietin (TSLP), and eosinophil cationic protein (Ecp). The underlying mechanism of RL and RP on the inhibition of AD symptom in offspring was closely associated with the alterations of the gut microbiota community in offspring, including an increase in Ligilactobacillus and Bacteroides. This study implies that RL and RP hold the potential to reduce the risk of AD in offspring via gut-mammary axis during the pregnancy and lactation period.

Interferon as an immunoadjuvant to enhance antibodies following influenza B infection and vaccination in ferrets

Despite annual vaccination, influenza B viruses (IBV) continue to cause significant morbidity and mortality in humans. We have found that IBV infection resulted in a weaker innate and adaptive immune response than influenza A viruses (IAV) in ferrets. To understand and overcome the weak immune responses to IBV in ferrets, we administered type-I or type-III interferon (IFN) to ferrets following infection or vaccination and evaluated their effects on the immune response. IFN signaling following viral infection plays an important role in the initial innate immune response and affects subsequent adaptive immune responses. In the respiratory tract, IFN lambda (IFNL) has regulatory effects on adaptive immunity indirectly through thymic stromal lymphopoietin (TSLP), which then acts on immune cells to stimulate the adaptive response. Following IBV infection or vaccination, IFN treatment (IFN-Tx) upregulated gene expression of early inflammatory responses in the upper respiratory tract and robust IFN, TSLP, and inflammatory responses in peripheral blood cells. These responses were sustained following challenge or vaccination in IFN-Tx animals. Serum IFNL and TSLP levels were enhanced in IFN-Tx animals following challenge/rechallenge over mock-Tx; however, this difference was not observed following vaccination. Antibody responses in serum of IFN-Tx animals following IBV infection or vaccination increased more quickly and to higher titers and were sustained longer than mock-Tx animals over 3 months. Following rechallenge of infected animals 3 months post treatment, antibody levels remained higher than mock-Tx. However, IFN-Tx did not have an effect on antibody responses following challenge of vaccinated animals. A strong direct correlation was found between TSLP levels and antibody responses following challenge-rechallenge and vaccination-challenge indicating it as a useful tool for predicting adaptive immune responses following IBV infection or vaccination. The effects of IFN on strengthening both innate and adaptive responses to IBV may aid in development of more effective treatments following infection and improved influenza vaccines.

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.

Expression of Epithelial Alarmin Receptor on Innate Lymphoid Cells Type 2 in Eosinophilic Chronic Obstructive Pulmonary Disease.

Studies have shown that eosinophilic COPD (eCOPD) is a distinct phenotype of the disease. It is well established that innate lymphoid cells are involved in the development of eosinophilic inflammation. Interleukin(IL)-25, thymic stromal lymphopoietin (TSLP) and IL-33 are a group of cytokines produced by epithelium in response to danger signals, e.g., cigarette smoke, and potent activators of ILC2s. In the present study, we examined circulating and sputum ILC2 numbers and expression of intracellular IL-5 as well as receptors for TSLP, IL-33 and IL-25 by ILC2s in non-atopic COPD patients with and without (neCOPD) airway eosinophilic inflammation and healthy smokers. In addition, we examined the association between ILC2s and clinical indicators of COPD burden (i.e., symptom intensity and risk of exacerbations). ILC2s were enumerated in peripheral blood and induced sputum by means of flow cytometry. We noted significantly greater numbers of airway IL-5+ILC2s and TSLPR+ILC2s in eCOPD compared with neCOPD (p < 0.05 and p < 0.01, respectively) and HSs (p < 0.001 for both). In addition, we showed that IL-5+ILC2s, IL-17RB+ILC2s and ST2+ILC2s are significantly increased in the sputum of eCOPD patients compared with HSs. In all COPD patients, sputum ILC2s positively correlated with sputum eosinophil percentage (r = 0.48, p = 0.002). We did not find any significant correlations between sputum ILC2s and dyspnea intensity as measured by the modified Medical Research Council scale (mMRC) and symptom intensity measured by the COPD Assessment Test (CAT). These results suggest the involvement of epithelial alarmin-activated ILC2s in the pathobiology of eosinophilic COPD.

ACUTE EOSINOPHILIC APPENDICITIS IN A CHILD WITH NORMAL TOTAL LEUKOCYTE COUNT AND ABSOLUTE EOSINOPHILIC COUNT

Abstract Introduction/Objective Eosinophilic appendicitis is a rare condition with a reported incidence of 0.03% to 1.2%, and often presents with clinical manifestations indistinguishable from acute appendicitis. Eosinophilic appendicitis may be associated with a localized allergic phenomenon. Methods/Case Report We present a 13-year-old male with ~24-hour history of constipation who was brought to the emergency department because of right lower quadrant abdominal pain, nausea, and vomiting. He was afebrile and had no antecedent of atopy or parasitic infestation. Laboratory investigation revealed an elevated C-reactive protein: 0.7 mg/dL [0.0-0.3]; mildly decreased hemoglobin: 12.2 g/dL [12.6 -16.8]; normal white blood cell count: 9.7 x10 3/mcL [3.2-10.6]; eosinophil count:1.7% [&amp;lt;5] and mildly elevated monocyte count: 0.9 x103/mcL [0.2-0.7]. Ultrasound examination revealed a non-compressible 7mm in diameter hyperemic appendix. The laparoscopic appendectomy specimen measured 9.5 cm long by 0.8 cm in diameter. The serosa was focally congested and there was mild mural thickening but no obvious sign of active appendicitis. Microscopic examination showed focally abundant mucosal eosinophils and a considerable sprinkling of eosinophils throughout the muscularis propria. No intraluminal parasite or neutrophilic associated mucosal damage was seen. The final diagnosis was: Acute Eosinophilic Appendicitis. Results (if a Case Study enter NA) N/A Conclusion Among the many and still intriguing causes of appendicitis is acute eosinophilic appendicitis. Eosinophils exert homeostatic roles in the normal host and pathological eosinophil-mediated processes over different tissues and their varied milieu. While this patient did not have any evidence of allergy, parasitic infestation, or elevated eosinophilic count in his work up, the presentation of acute appendicitis without an increase in total leukocytic count may alert for the possibility of an eosinophilic appendicitis. Conceivably, eosinophil mediators, such as IL-5, IL-33, granulocyte–macrophage colony-stimulating factor, thymic stromal lymphopoietin, and eotaxin-1 determine eosinophil behavior in a rarified appendix microenvironment.

Regulation of Airway Epithelial-Derived Alarmins in Asthma: Perspectives for Therapeutic Targets.

Asthma is a chronic respiratory condition predominantly driven by a type 2 immune response. Epithelial-derived alarmins such as thymic stromal lymphopoietin (TSLP), interleukin (IL)-33, and IL-25 orchestrate the activation of downstream Th2 cells and group 2 innate lymphoid cells (ILC2s), along with other immune effector cells. While these alarmins are produced in response to inhaled triggers, such as allergens, respiratory pathogens or particulate matter, disproportionate alarmin production by airway epithelial cells can lead to asthma exacerbations. With alarmins produced upstream of the type 2 inflammatory cascade, understanding the pathways by which these alarmins are regulated and expressed is critical to further explore new therapeutics for the treatment of asthmatic patients. This review emphasizes the critical role of airway epithelium and epithelial-derived alarmins in asthma pathogenesis and highlights the potential of targeting alarmins as a promising therapeutic to improve outcomes for asthma patients.

Acetamiprid elicits oxidative stress, pro-inflammatory response, and cellular proliferation in human bronchial epithelial cells in vitro and in silico: alleviative implications of the mixture of heat-killed Lactobacillus strains

BackgroundAcetamiprid (ACE), a neonicotinoid insecticide, has been extensively used to control pests in agricultural and industrial environments. It has been reported that ACE is detrimental to the lungs. Nevertheless, the extent to which the activation of oxidative stress, inflammation, and cellular proliferation contributes to the pulmonary toxicity induced by ACE exposure remains insufficiently understood. This study explored the mechanism of toxicological consequences after ACE exposure in bronchial epithelial cells (BEAS-2B cells). The research also examined the potential ameliorative effects of the mixture of heat-killed Lactobacillus delbrueckii and Lactobacillus fermentum (HKL) on the toxicities of ACE.ResultsFollowing 14 days of exposure to ACE at 0.5 and 1 μM, oxidative stress was induced, as evidenced by the decreased levels of reduced glutathione, catalase, glutathione peroxidase, and superoxide dismutase, along with increased levels of malondialdehyde. Also, ACE exposure results in overexpression and raised protein levels of the IL-25, NF-κB1, NF-κB2, IL-33, TSLP, and NF-κB target genes, which induce inflammatory responses. In addition, ACE boosted Ki-67-positive BEAS-2B cells. The molecular docking of ACE with target genes and their proteins demonstrated a potent binding affinity, further supported by the presence of hydrophobic contacts, electrostatic interactions, and hydrogen bonds. The post-treatment of HKL following the ACE (1 μM) exhibited its antioxidant, anti-inflammatory, and antiproliferative activities in suppressing ACE-induced toxicity.ConclusionsOur research revealed that ACE toxicity in BEAS-2B cells is caused by driving oxidative stress, pro-inflammatory response, and cellular proliferation. This study would give us a strategy to alleviate ACE-induced lung impairment by heat-killed probiotic supplements. As a result, dietary supplements that contain these microorganisms may potentially be beneficial in countries with high levels of pesticide contamination.

IL-7Rα on CD4+ T cells is required for their survival and the pathogenesis of experimental autoimmune encephalomyelitis

BackgroundThe IL-7 receptor alpha (IL-7Rα) binds both IL-7 and thymic stromal lymphopoietin (TSLP). IL-7Rα is essential for the development and survival of naive CD4+ T cells and their differentiation to effector/memory CD4+ T cells. Mice lacking IL-7Rα have severe lymphopenia and are resistant to experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis. However, it has been reported that IL-7Rα on peripheral CD4+ T cells is disposable for their maintenance and EAE pathogenesis, which does not align with the body of knowledge on the role of IL-7Rα in the biology of CD4+ T cells. Given that a definitive study on this important topic is lacking, we revisited it using a novel approach, an inducible knockout of the IL-7Rα gene in CD4+ T cells.MethodsWe generated Il7rafl/fl/CD4CreERT2 double transgenic mouse line (henceforth CD4ΔIl7ra), susceptible to tamoxifen-induced knockout of the IL-7Rα gene in CD4+ T cells. CD4ΔIl7ra mice were immunized with MOG35 − 55 for EAE induction and monitored for disease development. The expression of IL-7Rα, CD4+ T cell numbers, and MOG35 − 55-specific CD4+ T cell response was evaluated in the central nervous system (CNS) and lymphoid tissues by flow cytometry. Additionally, splenocytes of CD4ΔIl7ra mice were stimulated with MOG35 − 55 to assess their proliferative response and cytokine production by T helper cells.ResultsLoss of IL-7Rα from the surface of CD4+ T cells in CD4ΔIl7ra mice was virtually complete several days after tamoxifen treatment. The loss of IL-7Rα in CD4+ T cells led to a gradual and substantial decrease in their numbers in both non-immunized and immunized CD4ΔIl7ra mice, followed by slow repopulation up to the initial numbers. CD4ΔIl7ra mice did not develop EAE. We found a decrease in the total numbers of TNF-, IFN-γ-, IL-17 A-, and GM-CSF-producing CD4+ T cells and regulatory T cells in the spleens and CNS of immunized CD4ΔIl7ra mice. Tracking MOG35 − 55-specific CD4+ T cells revealed a significant reduction in their numbers in CD4ΔIl7ra mice and decreased proliferation and cytokine production in response to MOG35 − 55.ConclusionOur study demonstrates that IL-7Rα on peripheral CD4+ T cells is essential for their maintenance, immune response, and EAE pathogenesis.

Thymic stromal lymphopoietin signaling in B cells from progenitors to plasma cells.

Thymic stromal lymphopoietin (TSLP) is an established pleotropic alarmin cytokine that is generated at barrier tissues to induce type 2 immune responses, but its role in regulating the diversity of B cells is poorly understood. Here, we will highlight the key findings that underpin our limited understanding of the role TSLP in modulating different stages of B cell development. We will also provide an overview of how TSLP drives B cell-mediated immune disease and how novel TSLP-blocking biologics could be used to modulate B cell responses. TSLP is critical for the regulation, diversity, and longevity of humoral immunity.