From the AGA Journals

VIP an unwelcome contributor to eosinophilic esophagitis

 

Key clinical point: VIP appears to play an important role in the pathogenesis of eosinophilic esophagitis (EoE).

Major finding: Neurally derived VIP and its interaction with the CRTH2 receptor appear to recruit eosinophils and mast cells into the esophageal mucosa.

Data source: In vitro studies of human EoE biopsy samples and in vivo studies in mouse models of EoE.

Disclosures: The work was supported in part by grants from the National Institutes of Health and the Tulane Edward G. Schlieder Educational Foundation. Senior author Anil Mishra, PhD, disclosed serving as a consultant for Axcan Pharma, Aptalis, Elite Biosciences, Calypso Biotech SA, and Enumeral Biomedical. The remaining authors disclosed no conflicts of interest.

Source: Verma AK et al. Cell Mol Gastroenterol Hepatol. 2018;5[1]:99-100.e7.

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Closing the gaps in our understanding
Edda Fiebiger, PhD

The rapid increase in the incidence of pediatric and adult eosinophilic esophagitis (EoE) draws immediate attention to the importance of studying the mechanisms underlying this detrimental condition. The lack of preventive or curative therapies for EoE further underscores the importance of research that addresses gaps in our understanding of how eosinophilic inflammation of the esophagus is regulated on the molecular and cellular level. EoE is classified as an allergic immune disorder of the gastrointestinal tract and is characterized by eosinophil-rich, chronic Th2-type inflammation of the esophagus.
In this recent publication, the laboratory of Anil Mishra, PhD, showed that vasoactive intestinal peptide (VIP) serves as a potent chemoattractant for eosinophils and promotes accumulation of these innate immune cells adjacent to nerve cells in the muscular mucosa. Increased VIP expression was documented in EoE patients when compared to controls, and the authors identified the chemoattractant receptor homologous molecule expressed on Th2 lymphocytes (CRTH2) as a main binding receptor for VIP. Interestingly, CRTH2 was not only found to be expressed on eosinophils but also on tissue mast cells – another innate immune cell type that significantly contributes to the inflammatory tissue infiltrate in EoE patients. Based on the human findings, the authors tested whether VIP plays a major role in recruiting eosinophils and mast cells to the inflamed esophagus and whether CRTH2 blockade can modulate experimental EoE. Indeed, EoE pathology improved in animals that were treated with a CRTH2 antagonist.
In conclusion, these observations suggest that inhibiting the VIP-CRTH2 axis may serve as a therapeutic intervention pathway to ameliorate innate tissue inflammation in EoE patients.

Edda Fiebiger, PhD, is in the department of pediatrics in the division of gastroenterology, hepatology and nutrition at Boston Children’s Hospital, as well as in the department of medicine at Harvard Medical School, also in Boston. She had no disclosures.


 

FROM CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY

Vasoactive intestinal peptide (VIP) appears to play an important role in the pathology of eosinophilic esophagitis (EoE) by recruiting mast cells and eosinophils that contribute to EoE’s hallmark symptoms of dysphagia and esophageal dysmotility, investigators reported in the February issue of Cellular and Molecular Gastroenterology and Hepatology.

Blocking one of three VIP receptors – chemoattractant receptor-homologous molecule expressed on Th2 (CRTH2) – could reduce eosinophil infiltration and mast cell numbers in the esophagus, wrote Alok K. Verma, PhD, a postodoctoral fellow at Tulane University in New Orleans, and his colleagues.

“We suggest that inhibiting the VIP–CRTH2 axis may ameliorate the dysphagia, stricture, and motility dysfunction of chronic EoE,” they wrote in a research letter to Cellular and Molecular Gastroenterology and Hepatology.

Several cytokines and chemokines, notably interleukin-5 and eotaxin-3, have been fingered as suspects in eosinophil infiltration, but whether chemokines other than eotaxin play a role has not been well documented, the investigators noted.

They hypothesized that VIP may be a chemoattractant that draws eosinophils into perineural areas of the muscular mucosa of the esophagus.

To test this idea, they looked at VIP-expression in samples from patients both with and without EoE and found that VIP expression was low among controls (without EoE); they also found that eosinophils were seen to accumulate near VIP-expressing nerve cells in biopsy samples from patients with EoE.

When they performed in vitro studies of VIP binding and immunologic functions, they found that eosinophils primarily express the CRTH2 receptor rather than the vasoactive intestinal peptide receptor 1 (VPAC-1) or VPAC-2.

They also demonstrated that VIP’s effects on eosinophil motility was similar to that of eotaxin and that, when they pretreated eosinophils with a CRTH2 inhibitor, esoinophil motility was hampered.

The investigators next looked at biopsy specimens from patients with EoE and found that eosinophils that express CRTH2 accumulated in the epithelial mucosa.

To see whether (as they and other researchers had suspected) VIP and its interaction with the CRTH2 receptor might play a role in mast cell recruitment, they performed immunofluorescence analyses and confirmed the presence of the CRTH2 receptor on tryptase-positive mast cells in the esophageal mucosa of patients with EoE.

“These findings suggest that, similar to eosinophils, mast cells accumulate via interaction of the CRTH2 receptor with neutrally derived VIP,” they wrote.

Finally, to see whether a reduction in peak eosinophil levels in patients with EoE with a CRTH2 antagonist – as seen in prior studies – could also ameliorate the negative effects of mast cells on esophageal function, they looked at the effects of CRTH2 inhibition in a mouse model of human EoE.

They found that, in the mice treated with a CRTH2 blocker, each segment of the esophagus had significant reductions in both eosinophil infiltration and mast cell numbers (P less than .05 for each).

The work was supported in part by grants from the National Institutes of Health and the Tulane Edward G. Schlieder Educational Foundation. Senior author Anil Mishra, PhD, disclosed serving as a consultant for Axcan Pharma, Aptalis, Elite Biosciences, Calypso Biotech SA, and Enumeral Biomedical. The remaining authors disclosed no conflicts of interest.

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