New insight into the onset, progression, and treatment of eosinophilic esophagitis (EoE)

We provided adequate data to support the crucial role of IL-18 in the development of EoE and showed the pretreatment with NLRP3 and caspase-1 inhibitors such as MCC950, BHB, and VX-765 protects against both food allergen- and aeroallergen-induced EoE pathogenesis in an EoE experimental model.
Published in Protocols & Methods
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Eosinophilic esophagitis (EoE) is an increasingly common disorder that causes chronic inflammation and progressive dysfunction of the esophagus. It is characterized by thickening and scarring (fibrosis) of the epithelial and subepithelial esophageal tissues and is strongly linked to food allergies. The prevalence of EoE has been growing over the past 25 years, particularly among pediatric patients. 1

Eosinophils are a class of white blood cells that are present in unusually high levels in EoE. Some EoE symptoms, like abdominal pain and vomiting, can mimic gastroesophageal reflux disease (GERD). Other symptoms, such as food impaction, dysphagia (difficulty swallowing), and chest pain, are also common among patients with inflammatory or fibrotic blockages of the esophagus. A healthy esophagus has no eosinophils, so histological analysis indicating that more than 15 eosinophils per high power field (eos/hpf) are present in esophageal mucosa of patients constitutes an official pathological diagnosis of EoE in patients. 2

The underlying pathophysiology associated with EoE includes inflammation, fibrous structural alterations, and motor abnormalities. The early developmental stages of EoE are characterized by fibrosis caused by the protein transforming growth factor b (TGF-b) along with an abundance of immune proteins called cytokines, likely produced largely by T-helper 2 (Th2) cells. This type of immune response is associated with an abnormally high release of inflammatory cytokines like interleukins (e.g., IL-4, IL-5, IL-13, IL-33) and eotaxin-3; however, TH2 cells, eosinophils, mast cells, and IgE-producing B cells can also lead to esophageal inflammation during EoE. 3

Traditional EoE treatments include dietary changes, proton pump inhibitor medications (PPIs, also frequently prescribed for GERD), and oral topical corticosteroids (TCS), all of which can lead to clinical and histological remission from EoE. Although the first medication specifically designed to address EoE (orodispersible budesonide) was recently given the green light in Europe, and the monoclonal antibody drug dupilumab, which inhibits the production of some cytokines, has also recently become available as a treatment for EoE in the United States, dietary changes to limit exposure to certain food antigens (particularly dairy, wheat, soy, eggs, nuts, and seafood/shellfish) can be very effective and should be a first-line treatment. For some severe cases, endoscopic dilatation (a procedure in which a clinician carefully and gradually stretches the esophagus) may be the only treatment that brings relief in the long term. Abnormal genetic variations associated with EoE suggest that the Th2 family of cytokines are active in setting the stage for EoE, but Phase III clinical trials evaluating cytokine neutralizers like anti-IL-5, anti-IL-13, and anti-IL-4Rα have not yet proven very effective in treating EoE. 4

In the July 31st, 2023 issue of the Nature group of journal-Communications Biology, from the group of Prof. Anil Mishra including first author Chandra Sekhar Yadavalli, PhD from the Department of Medicine/Pulmonary, Tulane University School of Medicine, Eosinophilic Disorder Center in New Orleans published a study implicating the NLRP3/caspase-1/IL-18 pathway (a series of specific interactions among molecules that cause changes in cells) in the onset and progression of EoE. They induced experimental EoE in mice using food (Corn) and aero-allergens (Aspergillus fumigatus) and reported that a new NLRP3/Caspase-1-IL-18 pathway involved in EoE in initiation and treatment with the antagonist of respective molecules inhibit this pathway to improve EoE symptoms in the mice. The investigators provided the evidences that even mice overexpressing the cytokine IL-5 do not show much EoE symptoms like intraepithelial cells, eosinophil degranulation, basal cell proliferation, and collagen deposition in the epithelial mucosa, which are unusually observed in human EoE. They also provided the evidences that rIL-18 delivery also promoted characteristics of EoE in ΔdblGATA mice that do not have naturally occurring eosinophils in the blood and tissues, including esophagus. These findings are indicative of an important role for Th1 cytokine IL-18 in the initiation of EoE, a  member of the IL-1 family of cytokines. IL-5 only ameliorate in the proliferation and survival of eosinophils and IL-13 in promoting pathogenesis.  Their investigations found that immune cells like antigen-presenting cells and epithelial cells are responsible for the increased production of NLRP3 regulated IL-18 that initiate EoE, rather than Th2 cells or the chemokine eotaxin-3. The rationale that Th2 cells or eotaxins are not critical in initiating the EoE, based on the previous reports that naïve esophagus has highly induced baseline eotaxins and devoid of eosinophils. In addition, CD4+, CD8+ T cells-deficient and eotaxins-deficient mice are not protected from the induction of allergen-induced EoE. Furthermore, eotaxin-3 is not detected in mice, but still accumulates eosinophils in epithelial mucosa following the injection of rIL-18, indicating a limited or no role of even eotaxin-3 in EoE pathogenesis.

Fig.1 Colocalization of induced NLRP3 regulated IL-18 in Cytokeratin expressed epithelial cells in the tissue biopsies of human EoE (A). Western blot analysis indicated that allergen induced EoE characteristic proteins are down regulated in experimental EoE (B)

The Mishra lab at Tulane Medical Center, New Orleans LA (USA) has previously reported that IL-18 has a capability to generate eosinophils that express the IL-5-independent subgroup of eosinophils that have protein-coding gene CD274 and also transform IL-5-generated naive eosinophils into CD274+ pathogenic eosinophils. 5 They  also found evidence that a similar NLRP3-IL-18 pathway is operational in human EoE (Fig.1), and that the gene NLRP3, along with inhibitors N-[ (1,2,3,5,6,7-hexahydro-s-indacen-4-yl) amino] carbonyl]-4-(1-hydroxy-1-methylethyl)-2-furansulfonamide (MCC950), β-hydroxybutyrate (BHB), the caspase-1 inhibitor belnacasan (VX-765), and neutralizing IL-18 are promising therapeutic targets for EoE. These inhibitors are ideal drug candidates, since they are well characterized and already available from pharmaceutical companies.

The Mishra has filed an international patent application to test these compounds in a double-blind clinical trial as a future treatment strategy for EoE. They believe that these trials will establish the importance of NLRP3 regulated IL-18 in promoting EoE pathogenesis and protect IL-5-generated naïve eosinophils that home prenatally in the human body and are critical in maintaining innate immunity and development during different stages of life.

 

 Chandra Sekhar Yadavalli, PhD and Anil Mishra, PhD

John W. Deming Department of Medicine, Section of Pulmonary Diseases, Tulane Eosinophilic Disorder Center (TEDC), Tulane University School of Medicine, New Orleans, LA, USA.

References

  1. Bredenoord, A. J., Patel, K., Schoepfer, A. M., Dellon, E. S., Chehade, M., Aceves, S. S., ... & Jacob-Nara, J. A. (2022). Disease burden and unmet need in eosinophilic esophagitis. The American Journal of Gastroenterology117(8), 1231-1241.
  2. Straumann, A., & Katzka, D. A. (2018). Diagnosis and treatment of eosinophilic esophagitis. Gastroenterology, 154(2), 346-359.
  3. O’Shea, K. M., Aceves, S. S., Dellon, E. S., Gupta, S. K., Spergel, J. M., Furuta, G. T., & Rothenberg, M. E. (2018). Pathophysiology of eosinophilic esophagitis. Gastroenterology154(2), 333-345.
  4. Uchida, A. M., Burk, C. M., Rothenberg, M. E., Furuta, G. T., & Spergel, J. M. (2023). Recent advances in the treatment of eosinophilic esophagitis. The Journal of Allergy and Clinical Immunology: In Practice.
  5. Mishra, A., Majid, D., Kandikattu, H. K., Yadavalli, C. S., & Upparahalli Venkateshaiah, S. (2022). Role of IL‐18‐transformed CD274‐expressing eosinophils in promoting airway obstruction in experimental asthma. Allergy77(4), 1165-1179.

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