IL-4/IL-13 axis as therapeutic targets in allergic rhinitis and asthma

Husna, Siti Muhamad Nur; Shukri, Norasnieda Md; Ashari, Noor Suryani Mohd; Wong, Kah Keng

doi:10.7717/peerj.13444

Cited by 42 publications

(26 citation statements)

References 101 publications

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“…Moreover, alongside investigations into the NLRP3 pathway, attention has been directed toward understanding other molecular cascades involved in allergic responses. Various studies have examined the role of different cytokines, such as IL‐4, IL‐5, and IL‐13, and their influence on immune cell differentiation and activation in rhinitis 17,18 . Additionally, research has spotlighted the involvement of signaling pathways like the NF‐κB pathway, MAPK pathway, and PI3K/AKT pathway in the modulation of immune responses associated with rhinitis 19–21 …”

Section: Discussionmentioning

confidence: 99%

“…15,16 The immune cell differentiation and activation in rhinitis. 17,18 Additionally, research has spotlighted the involvement of signaling pathways like the NF-κB pathway, MAPK pathway, and PI3K/AKT pathway in the modulation of immune responses associated with rhinitis. [19][20][21] The findings from earlier investigations into macrophage…”

Section: Nlrp3 Inhibitor Mcc950 Effectively Alleviates Ova-induced Armentioning

confidence: 99%

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Immunomodulation in allergic rhinitis: Insights from Th2 cells and NLRP3/IL‐18 pathway

Hu,

Liu,

Jing

et al. 2024

Cell Biochemistry & Function

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Allergic rhinitis (AR) is characterized by nasal symptoms such as rubbing and sneezing, often triggered by allergen exposure. The purpose of this study is to dissect the roles of NLRP3‐mediated immune modulation and macrophage pyroptosis in modulating T cell differentiation within the context of ovalbumin (OVA)‐induced AR in mice. OVA‐induced AR was established in mice, evaluating nasal symptoms, macrophage infiltration, cytokine levels, and T cell differentiation. Manipulations using NLRP3−/−, ASC−/− mice, clodronate liposome treatment, and NLRP3 inhibitor MCC950 were performed to assess their impact on AR symptoms and immune responses. Following OVA stimulation, increased nasal symptoms were observed in the OVA group along with augmented GATA3 expression and elevated IL‐4 and IL‐1b levels, indicative of Th2 polarization and cellular pyroptosis involvement. NLRP3−/− and ASC−/− mice exhibited reduced CD3+ T cells post OVA induction, implicating cellular pyroptosis in AR. Macrophage depletion led to decreased IgE levels, highlighting their involvement in allergic responses. Further investigations revealed enhanced macrophage pyroptosis, influencing Th1/Th2 differentiation in AR models. IL‐18 released through NLRP3‐mediated pyroptosis induced Th2 differentiation, distinct from IL‐1b. Additionally, MCC950 effectively mitigated AR symptoms by modulating Th2 responses and reducing macrophage infiltration. This comprehensive study unravels the pivotal role of NLRP3‐mediated immune modulation and macrophage pyroptosis in Th1/Th2 balance regulation in OVA‐induced AR. Targeting NLRP3 pathways with MCC950 emerged as a promising strategy to alleviate AR symptoms, providing insights for potential therapeutic interventions in AR management.

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Section: Discussionmentioning

confidence: 99%

Section: Nlrp3 Inhibitor Mcc950 Effectively Alleviates Ova-induced Armentioning

confidence: 99%

Immunomodulation in allergic rhinitis: Insights from Th2 cells and NLRP3/IL‐18 pathway

Hu,

Liu,

Jing

et al. 2024

Cell Biochemistry & Function

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“…According to the pathogenesis of AR, type 2 immunity plays an important role [4]. Thus, type 2 cytokines, such as IL-4, IL-5, and IL-13, are promising therapeutical targets for AR and also other allergic diseases, such as asthma and atopic dermatitis [7,9]. Unfortunately, according to our literature review, there were currently no RCTs investigating the safety of anti-IL-5/5Ra mAbs including mepolizumab, reslizumab and benralizumab, or anti-IL-13 mAbs including lebrikizumab and tralokinumab in AR.…”

Section: Discussionmentioning

confidence: 99%

“…Given traditional treatment regimens are not always efficacious, there is certainly a role for newer therapies, such as monoclonal antibodies (mAbs) [6]. As the progress of researches on the immunopathogenic mechanisms of AR, mAbs blocking essential disease-causing factors are proven to have promising therapeutic effects [7][8][9][10][11][12]. However, the overall safety of mAbs is still in question, with a poorly understanding of the underlying mechanisms of many mAb-related adverse reactions [13].…”

Section: Introductionmentioning

confidence: 99%

Adverse Events for Monoclonal Antibodies in Patients with Allergic Rhinitis: A Systematic Review and Meta-Analysis of Randomized Clinical Trials

Lin

Wang

Zhu

et al. 2023

JCM

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(1) Background: Allergic rhinitis (AR) is a common disease in otolaryngology and novel biological therapies are required for clinical needs. To assess the tolerability of monoclonal antibodies, justifying their clinical applications, we presented a comprehensive safety profile of biologics in AR; (2) Methods: A systematic literature search was conducted following PRISMA guidelines for randomized clinical trials comparing monoclonal antibodies and placebo in AR. PubMed, Web of Science, Medline, and Cochrane were searched up until 9 January 2023. Among 3590 records in total, 12 studies with more than 2600 patients were included. Quality was assessed for all studies using Cochrane risk-of-bias tool for randomized trials, and subgrouped meta-analysis was performed; (3) Results: We accomplished an up-to-date literature overview and analysis on adverse events of monoclonal antibodies in AR. Total, common, severe, discontinuation-causing, and serious adverse events failed to reach statistical significance. Country was an essential factor for heterogeneity, and urticaria was the adverse event at highest risk (RR 2.81, 95% CI 0.79–9.95); (4) Conclusions: Monoclonal antibodies are considered well tolerated and relatively safe in patients with AR. The regions of patients and hypersensitive adverse reactions such as urticaria require a special caution in biological treatments in AR.

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“…Dysregulated Th2 cells are the main drivers of allergic asthma and rhinitis (4). The inflammatory responses, led by excess mucus production and smooth muscle contraction in the respiratory tract, are predominantly mediated by IL-13, with IL-4 playing second fiddle (5, 6). The co-expression of IL-4 and IL-13 in Th2 cells results in the convergence of their roles, leading to significant functional overlap (7).…”

Section: Introductionmentioning

confidence: 99%

Calcitriol impairs the secretion of IL-4 and IL-13 in Th2 cells via modulating VDR-Gata3-Gfi1 axis

Biswas,

Chattopadhyay,

Hazra

et al. 2023

Preprint

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The bioactive form of vitamin D, calcitriol exerts its biological function by binding to its cognate receptor VDR. Although calcitriol increased the expression of VDR in murine Th2 cells, IL-4 and IL-13 secretion were diminished significantly. Interestingly, IL-10 secretion increased post calcitriol treatment. The expression of Th2 master regulator Gata3 was attenuated by calcitriol. However, the expression of Gfi1, a transcriptional repressor, that prevents activated CD4+ T cells from triggering the Th1 program, was attenuated too in the presence of calcitriol. Ectopic expression of either Gfi1 or VDR impaired the secretion of IL-13 but not IL-4 in Th2 cells. Ecr, a common conserved region, enhanced the transactivation of bothIl4, andIl13promoter, which got attenuated in the presence of calcitriol. Calcitriol interfered withIl13promoter activation but notIl4promoter activation, which was Gata3-dependent but Ecr-independent. As a repressor Gfi1 significantly impairedIl13promoter activation; addition of calcitriol failed to alter the promoter activity. In murine Th2 cells, VDR interacted with Gata3 but not Gfi1. Calcitriol augmented the recruitment of VDR toIl13promoter and Ecr regions, exceptIl4promoter. Gata3 recruitment was significantly impaired atIl13and Ecr locus in the presence of calcitriol but increased atIl4promoter. However, in the presence of calcitriol the overall recruitment of Gfi1 remained unchanged atIl4but increased atIl13locus in Th2 cells. Calcitriol elicited distinct histone modifications atIl4andIl13gene loci. Together, our studies elucidated the molecular mechanisms behind calcitriol-mediated regulation of Th2 cell differentiation.Abstract Figure

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IL-4/IL-13 axis as therapeutic targets in allergic rhinitis and asthma

Cited by 42 publications

References 101 publications

Immunomodulation in allergic rhinitis: Insights from Th2 cells and NLRP3/IL‐18 pathway

Immunomodulation in allergic rhinitis: Insights from Th2 cells and NLRP3/IL‐18 pathway

Adverse Events for Monoclonal Antibodies in Patients with Allergic Rhinitis: A Systematic Review and Meta-Analysis of Randomized Clinical Trials

Calcitriol impairs the secretion of IL-4 and IL-13 in Th2 cells via modulating VDR-Gata3-Gfi1 axis

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