Role of gastrointestinal eosinophils in inflammatory bowel disease and intestinal tumours

doi:10.1016/j.bpg.2007.12.001

Best Practice & Research Clinical Gastroenterology

Volume 22, Issue 3, June 2008, Pages 537-549

https://doi.org/10.1016/j.bpg.2007.12.001 Get rights and content

Eosinophils have been implicated in the pathogenesis of inflammatory bowel disease (IBD). Immunohistopathological studies have revealed accumulation and activation of eosinophils in actively inflamed intestinal mucosa of Crohn's disease and ulcerative colitis patients. Elevated levels of chemokines relevant for eosinophil chemotaxis and mediator release from eosinophils can be detected in serum and faeces of patients with active IBD. Animal studies have revealed that abrogation of chemokines (such as eotaxin) promoting eosinophil chemotaxis and circulation results in decreased severity of murine experimental colitis, suggesting a pro-inflammatory role for eosinophils in IBD. Furthermore, selective deletion of certain eosinophil-specific granule products results in attenuation of experimental intestinal inflammation. Shortly after their initial discovery by Ehrlich, eosinophils have been associated with intestinal tumours. However, as only very few studies have addressed the role of eosinophils in intestinal cancerogenesis, their impact on intestinal tumour development remains obscure; in particular, functional data are missing.

Section snippets

Eosinophils: differentiation and homing to the gut

Eosinophils originate from the bone marrow from pluripotent stem cells. Interleukin-3 (IL-3), IL-5, and granulocyte/macrophage colony-stimulating factor (GM-CSF) are the most important cytokines in eosinophil development, while IL-5 is the most specific cytokine for the selective differentiation of progenitors to the eosinophil lineage.¹ In addition to its relevance in differentiation, IL-5 is an important stimulus for the release of eosinophils from the bone marrow into the peripheral

Accumulation of eosinophils in IBD

Various studies, including our own, have addressed the question of eosinophil numbers at sites of inflammation in IBD.25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 Almost all studies have revealed eosinophilic accumulation in the inflamed intestinal mucosa in IBD. Differences – and sometimes limitations – in the sample size, the choice of patient population, and different methods used to quantify eosinophils might explain the slight variations in the extent of eosinophilia in the published

Activation of eosinophils in IBD

The increased immunohistochemical staining of ECP using the EG2 antibody supposed to bind preferentially to ‘activated ECP’ indicates the activation status of eosinophils in IBD, which has been shown repeatedly by independent groups.27, 30, 32 In addition to assessing quantitative alterations in eosinophil counts in the mucosa of IBD patients, Bischoff et al investigated the activation status of eosinophils in IBD and eosinophilic gastroenteritis.²⁷ They studied sections of intestinal biopsies

Functional relevance of eosinophils in IBD

Basically all the data presented above derived from human studies are limited to descriptive data, or provide only indirect evidence of eosinophil involvement in IBD. Even with the knowledge of an increase in eosinophil mediators in IBD, we still do not know what effects these mediators will have in the intestinal mucosa. Basically, eosinophil granule cationic proteins are associated with tissue damage. However, at the same time they have been attributed to non-cytotoxic or at least more

Therapeutic approach to IBD and eosinophils

Therapeutic options in IBD are limited to either unspecific suppression of immune responses using steroids and/or immunosuppressants such as azathioprine, or blockade of tumour necrosis factor α (TNF-α), an important pro-inflammatory mediator in the context of IBD. Despite the development of new therapeutics such as TNF-α antibodies, glucocorticoids remain the treatment of choice for acute flares in both ulcerative colitis and Crohn's disease.⁵² They are highly effective agents in reducing

Eosinophils in intestinal neoplasia

Shortly after their initial description by Ehrlich, eosinophils were linked with malignancies.⁶⁴ In 1959, Yoon investigated eosinophil numbers in colonic and gastric adenocarcinomas. He reported a reduced mortality, especially during the first year after surgery, of patients with increased eosinophilic infiltration of the gastrointestinal tumours.⁶⁵ Based on these observations, Pretlow et al analysed the prognostic influence of infiltrating eosinophils on human colonic carcinomas with regard to

Summary and concluding remarks

In conclusion, IBD is associated with eosinophil accumulation at sites of active inflammation. Measurement of eosinophil granule products in faeces of patients with IBD correlates with disease severity and can be used as a predictor of a disease flare. However, despite the progress made in recent years, it is still unclear whether eosinophils have solely pro-inflammatory and deleterious effects on the mucosa in IBD, or whether they also exhibit protective effects. Data from genetically

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Eosinophils secrete toxic proinflammatory proteins such as eosinophil cationic protein (ECP), major basic protein, eosinophil protein X, eosinophil-derived neuroendotoxin, and eosinophil peroxidase. Elevated levels of these proteins in IBD patients damage intestinal tissues, insert pores into membranes of target cells, and increase smooth muscle reactivity by generating toxic oxygen radicals.13-17 Many studies based on animal models induced with colitis or transgenic knockout model studies have shed considerable light on the role of multiple genetic mutations as a trigger for IBD.
Ulcerative colitis and Crohn's disease are the 2 major phenotypes of inflammatory bowel disease (IBD), which are influenced by a complex interplay of immunological and genetic elements, though the precise etiology still remains unknown. With IBD developing into a globally prevailing disease, there is a need to explore new targets and a thorough understanding of the pathophysiological differences between the healthy and diseased gut could unearth new therapeutic opportunities. In this review, we provide an overview of the major aspects of IBD pathogenesis and thereafter present a comprehensive analysis of the gut pathophysiology leading to a discussion on some of the most promising targets and biologic therapies currently being explored. These include various gut proteins (CXCL-10, GATA-3, NKG2D, CD98, microRNAs), immune cells recruited to the gut (mast cells, eosinophils, toll-like receptors 2, 4), dysregulated proinflammatory cytokines (interleukin-6, -13, -18, -21), and commensal microbiota (probiotics and fecal microbiota transplantation). We also evaluate some of the emerging nonconventional therapies being explored in IBD treatment focusing on the latest developments in stem cell research, oral targeting of the gut-associated lymphoid tissue, novel anti-inflammatory signaling pathway targeting, adenosine deaminase inhibition, and the beneficial effects of antioxidant and nutraceutical therapies. In addition, we highlight the growth of biologics and their targets in IBD by providing information on the preclinical and clinical development of over 60 biopharmaceuticals representing the state of the art in ulcerative colitis and Crohn's disease drug development.
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9Role of gastrointestinal eosinophils in inflammatory bowel disease and intestinal tumours

Section snippets

Eosinophils: differentiation and homing to the gut

Accumulation of eosinophils in IBD

Activation of eosinophils in IBD

Functional relevance of eosinophils in IBD

Therapeutic approach to IBD and eosinophils

Eosinophils in intestinal neoplasia

Summary and concluding remarks

J Allergy Clin Immunol

J Allergy Clin Immunol

Blood

Semin Immunol

Am J Gastroenterol

Lancet

Am J Gastroenterol

Am J Gastroenterol

Am J Gastroenterol

Mayo Clin Proc

Am J Gastroenterol

Lancet

J Allergy Clin Immunol

Am J Gastroenterol

Blood

Am J Surg

Hum Pathol

Am J Gastroenterol

The eosinophil

Annu Rev Immunol

Mucosal immunity in Crohn's disease

Inflamm Bowel Dis

Mechanisms of disease: pathogenesis of Crohn's disease and ulcerative colitis

Nat Clin Pract Gastroenterol Hepatol

The fundamental basis of inflammatory bowel disease

J Clin Invest

CARD15/NOD2 mutations in Crohn's disease

Ann N Y Acad Sci

Genetic variation in DLG5 is associated with inflammatory bowel disease

Nat Genet

Evidence for association of OCTN genes and IBD5 with ulcerative colitis

Gut

Cooperation between interleukin-5 and the chemokine eotaxin to induce eosinophil accumulation in vivo

J Exp Med

Interleukin 5 deficiency abolishes eosinophilia, airways hyperreactivity, and lung damage in a mouse asthma model

J Exp Med

Fundamental signals that regulate eosinophil homing to the gastrointestinal tract

J Clin Invest

Human eotaxin is a specific chemoattractant for eosinophil cells and provides a new mechanism to explain tissue eosinophilia

Nat Med

A pathological function for eotaxin and eosinophils in eosinophilic gastrointestinal inflammation

Nat Immunol

The murine CCR3 receptor regulates both the role of eosinophils and mast cells in allergen-induced airway inflammation and hyperresponsiveness

Proc Natl Acad Sci U S A

Chemokines in inflammatory bowel disease

J Clin Pathol

Chemokines in gastrointestinal disorders

Curr Drug Targets

Enhanced production of monocyte chemotactic protein 3 in inflammatory bowel disease mucosa

Gut

Molecular cloning and characterization of a human eotaxin receptor expressed selectively on eosinophils

J Exp Med

9
Role of gastrointestinal eosinophils in inflammatory bowel disease and intestinal tumours