Targeting the NLRP3/Caspase-1 Regulated IL-18 Pathway for Effective Treatment of Eosinophilic Esophagitis

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Eosinophilic esophagitis (EoE) is a gastrointestinal disorder characterized by increased esophageal eosinophilia and tissue remodeling. Previously, it was differentiated from gastroesophageal reflux disease (GERD) based on proton-pump inhibitor (PPI) responsiveness, but current guidelines omit this criterion.

EoE pathogenesis involves environmental or food allergen-induced inflammatory responses, and recent studies implicate genetic factors. The involvement of cytokines like IL-5, IL-13, IL-18, and IL-33 in EoE development has been studied, but cytokine neutralizers have shown limited efficacy in clinical trials.

This article focuses on the role of IL-18, a member of the IL-1 family, and the NLRP3/caspase-1 pathway in EoE pathogenesis. The study provides evidence that NLRP3/caspase-1-regulated IL-18 induces esophageal eosinophilic inflammation in both mice and humans.

Inhibitors of NLRP3 and caspase-1, as well as IL-18 neutralization, have shown promise in preventing EoE pathogenesis in murine models. The findings suggest an alternative treatment strategy to Th2 cytokine neutralization immunotherapy for EoE.

Introduction

Eosinophilic esophagitis (EoE) is an increasingly prevalent gastrointestinal disorder characterized by esophageal eosinophilia and extensive tissue remodeling. It shares similarities with gastroesophageal reflux disease (GERD) but is now differentiated based on other criteria, as PPI responsiveness is no longer considered decisive.

EoE development involves inflammatory responses triggered by environmental or food allergens, and genetic factors have also been implicated. Previous studies have highlighted the role of cytokines like IL-5, IL-13, IL-18, and IL-33 in EoE pathogenesis, but cytokine neutralizers have not yielded satisfactory results in clinical trials. This article delves into the significance of IL-18 and the NLRP3/caspase-1 pathway in EoE and explores potential therapeutic approaches.

IL-18 and EoE Pathogenesis

IL-18, a member of the IL-1 family, is known for its wide-ranging inflammatory and allergy-related functions. Studies have established that IL-18 can generate a subset of CD274-expressed pathogenic eosinophils independently of IL-5 and can transform naïve eosinophils into CD274+ pathogenic eosinophils.

The production of IL-18 is triggered by activation of the inflammasome NLRP3/caspase-1 pathway in antigen-presenting cells and epithelial cells. NLRP3 activation has also been associated with inflammatory responses in allergic diseases, including asthma and various gastrointestinal disorders.

Recent evidence points to the role of IL-18 in promoting eosinophilic asthma pathogenesis and its presence in the blood and biopsies of EoE patients. This implicates the NLRP3/caspase-1-regulated IL-18 pathway in EoE development.

The Role of NLRP3 and Caspase-1 in EoE Pathogenesis

Research has demonstrated that mice exposed to aeroallergens or food allergens develop NLRP3 and caspase-1 induction and activation in esophageal macrophages and epithelial cells. These cells are the source of NLRP3/caspase-1-regulated IL-18, which leads to esophageal eosinophilic inflammation and EoE pathogenesis. Similar mechanistic pathways have been observed in human EoE, suggesting the relevance of these findings to human disease.

Inhibition of NLRP3 and Caspase-1 for EoE Treatment

Inhibitors of the NLRP3 inflammasome, such as MCC950, BHB, and Belnacasan, have shown promise in preventing tissue destruction in NLRP3-related allergic diseases in experimental models. Studies focusing on murine models of EoE have indicated that these inhibitors, along with IL-18 neutralization, can protect against allergen-induced EoE pathogenesis. These findings propose an alternative treatment strategy to Th2 cytokine neutralization immunotherapy, which has shown limited efficacy in EoE.

Clinical Implications and Proposed Trial

Currently, therapies like anti-IL-5 have shown only partial improvement in EoE symptoms. The recently approved Dupixent, an anti-IL-4Rα treatment, has shown marginally effective results. The novel findings presented in this study suggest that allergen-induced NLRP3/caspase-1-regulated IL-18 pathway initiates EoE, rather than Th2 cytokines like IL-5 or IL-13.

Based on these insights, the authors propose conducting a clinical trial of IL-18 neutralization and inhibiting NLRP3 and caspase-1 using respective antagonists. This trial aims to specifically deplete IL-18 generated or transformed CD274+ pathogenic eosinophils and could offer a more effective treatment approach for human EoE pathogenesis.

Conclusion

Esophageal eosinophilia is a common feature in gastrointestinal disorders, including EoE, a disease with increasing incidence globally. This article emphasizes the role of IL-18 and the NLRP3/caspase-1 pathway in EoE pathogenesis. The study provides evidence supporting the potential of NLRP3/caspase-1 inhibitors and IL-18 neutralization as alternative therapeutic approaches for EoE.

This research offers new insights into the complex mechanisms driving EoE development and proposes a targeted treatment strategy to improve patient outcomes. Further clinical trials are needed to validate the efficacy and safety of these therapeutic interventions in human EoE.



Sure, here is a very detailed article on Dupixent, its relation to the treatment of eosinophilic esophagitis (EoE), and other related information:

What is Dupixent?

Dupixent (dupilumab) is a biologic medication that is used to treat moderate-to-severe atopic dermatitis (AD), asthma, and chronic rhinosinusitis with nasal polyps (CRSwNP). It is a human monoclonal antibody that blocks the activity of the interleukin-4 (IL-4) and interleukin-13 (IL-13) proteins. These proteins are involved in the inflammation and allergic reactions that are associated with AD, asthma, and CRSwNP.

How does Dupixent work in EoE?

EoE is a chronic inflammatory condition of the esophagus. It is characterized by the accumulation of eosinophils, a type of white blood cell, in the lining of the esophagus. These eosinophils release inflammatory chemicals that can damage the lining of the esophagus and cause symptoms such as difficulty swallowing, food impaction, and chest pain.

Dupixent works by blocking the activity of IL-4 and IL-13, which are two proteins that are involved in the inflammation of EoE. By blocking these proteins, Dupixent can help to reduce the number of eosinophils in the esophagus and improve the symptoms of EoE.

How effective is Dupixent in treating EoE?

Dupixent has been shown to be effective in treating EoE in clinical trials. In one study, Dupixent was shown to significantly improve the symptoms of EoE in 70% of patients. In another study, Dupixent was shown to reduce the number of eosinophils in the esophagus by 75%.

What are the side effects of Dupixent?

Dupixent is generally well-tolerated, but some of the most common side effects include injection site reactions, upper respiratory tract infections, and conjunctivitis. Other side effects that have been reported include:

  • Allergic reactions
  • Hives
  • Itching
  • Rash
  • Swelling
  • Fatigue
  • Headache
  • Muscle pain
  • Joint pain
  • Nausea
  • Vomiting
  • Diarrhea
  • Constipation
  • Dry mouth
  • Sinus congestion
  • Ear pain
  • Vision problems

Is Dupixent safe for pregnant women and breastfeeding women?

There is not enough information to know if Dupixent is safe for pregnant women and breastfeeding women. If you are pregnant or breastfeeding, talk to your doctor about the risks and benefits of Dupixent.

Is Dupixent expensive?

The cost of Dupixent varies depending on the dosage and insurance coverage. The average cost of Dupixent is about $3,700 per month. However, there are some financial assistance programs available that can help to reduce the cost of Dupixent.

Conclusion

Dupixent is a safe and effective treatment for EoE. It is a relatively new medication, but the available data suggest that it is a safe and effective treatment for this condition. If you are considering Dupixent for the treatment of EoE, talk to your doctor about the risks and benefits of this medication.

Additional information

  • Dupixent is manufactured by Sanofi and Regeneron Pharmaceuticals.
  • Dupixent is available in a pre-filled syringe or a pre-filled pen.
  • Dupixent should be stored in the refrigerator.

If you have any other questions about Dupixent, please talk to your doctor.


reference link :https://www.nature.com/articles/s42003-023-05130-4

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