Inflamm Bowel Dis • Volume 25, Number 7, July 2019 1140 BASIC SCIENCE REVIEW ARTICLE Eosinophils in Inflammatory Bowel Disease Rhiannon T. Filippone, BSc,* Lauren Sahakian, BSc,* Vasso Apostolopoulos, PhD,* , and Kulmira Nurgali, PhD* ,†,‡, Clinical investigations in inflammatory bowel disease (IBD) patients have provided increasing evidence that eosinophils contribute to chronic intestinal inflammation. Accumulation of eosinophils in the gastrointestinal tract correlates with the variations of eosinophil regulatory mole- cules; however, their role in gastrointestinal dysfunction in IBD has not been fully elucidated. This review will describe the development and char- acterization of gastrointestinal eosinophils, mechanisms of eosinophil recruitment to the gastrointestinal tract. Moreover, the eosinophil-induced changes to the enteric nervous system associated with disease severity and gastrointestinal dysfunction will be analyzed with suggestive molecular pathways for enteric neuronal injury. Current and potential therapeutic interventions targeting eosinophils will be discussed. Key Words: Eosinophils, CCR3-eotaxin axis, enteric neurons, IBD INTRODUCTION Intestinal homeostasis requires a dynamic crosstalk between local leukocytes, intestinal cells and microbiota. 1 However, in gastrointestinal (GI) pathology such as inflamma- tory bowel disease (IBD), which includes ulcerative colitis (UC) and Crohn’s disease (CD), a dysregulated immune response associates with imbalanced intestinal microbiota, genetic pre- disposition, and susceptibility to environmental factors. 2–4 The intestinal milieu facilitates a cascade of inflammatory signals prompted by a cocktail of mediators that induce typical clinical symptoms such as abdominal pain, tenesmus, rectal bleeding, and gut hypersensitivity associated with GI dysfunction. 2, 5, 6 However, the direct mechanisms involved in IBD pathogenesis are loosely elucidated. Chronic GI abnormalities are thought to be a result of inflammation-associated damage to the en- teric nervous system (ENS) in patients with IBD. 6–8 The ENS is a division of the autonomic nervous system vital for regulating the primary functions of the GI tract, com- prising 2 major ganglionated plexi: the myenteric (Auerbach’s) plexus and the submucosal (Meissner’s) plexus. The myenteric plexus, positioned between the circular and longitudinal mus- cles, facilitates propulsive activity of the intestines (motility). The submucosal plexus, situated in the submucosa above the muscularis mucosae, advocates mucosal secretion and absorp- tion of the intestines. 9, 10 Substantial changes of enteric neu- ronal morphological and functional characteristics have been demonstrated in animal models of intestinal inflammation and IBD patients. These neuronal abnormalities cause altered neu- rotransmission to the GI muscles and mucosa attributing to a repertoire of clinical symptoms. 7, 11, 12 Enteric neuropathy and axonal damage in IBD patients and animal models of colitis are strongly mediated by native in- flammatory mediators in the GI tract. 7, 13–16 Biopsies from IBD patients demonstrated transmigration of polymorphonuclear (PMN) leukocytes infiltrating the intestinal walls, which cor- related with increased susceptibility to architectural damage. 17 Received for publications September 6, 2018; Editorial Decision January 27, 2019. From the *College of Health and Biomedicine, Institute for Health and Sport, Victoria University, Melbourne, Australia; † Department of Medicine Western Health, Melbourne University, Melbourne, Australia; ‡ Australian Institute for Musculoskeletal Science (AIMSS), Melbourne, Australia Supported by a Victoria University Research Support Grant. Address correspondence to: Kulmira Nurgali, College of Health and Biomedicine, Victoria University, Western Centre for Health Research & Education, 176 Furlong Road, St Albans, 3021, VIC, Australia. E-mail: kulmira.nurgali@vu.edu.au. Abbreviations: 5-HT, 5-Hydroxytryptamine; 5-HTP, 5-Hydroxytryptophan; ACh, Acetylcholine; AP-1, Activator protein-1; APC, Antigen presenting cells; C/EBP, CCAAAT/enhancer-binding protein; CCL11, Chemokine eotaxin-1; CCL24, Eotaxin-2; CCL26, Eotaxin-3; CCR, Chemokine receptor; CD, Cluster of differentiation; CD, Crohn’s disease; CGRP, Calcitonin gene-related peptide; ChAT, Choline acetyltransferase; COPD, Chronic obstructive pulmonary dis- order; DAPI, 4’,6-diamidino-2-phenylindole dihydrochloride; DC, Dendritic cell; DDC, Decarboxylase; ECC, Enterochromaffin cells; ECP, Eosinophil cat- ionic protein; EDN, Eosinophil-derived neurotoxin; ENS, Enteric nervous sys- tem; EPHCs, Eosinophil promoting hematopoietic cytokines; EPO, Eosinophil peroxidase; ETS, E26 transformation-specific; GI, Gastrointestinal; GM-CSF, Granulocyte monocyte-colony stimulating factor; GTAT-1, Erythroid transcrip- tion factors; H 2 O 2 , Hydrogen peroxide; IBD, Inflammatory bowel disease; ICAM, Intercellular adhesion molecule; IL, Interleukin; IL-13Rα1, IL-13 receptor alpha 1-chain; JKN, Jun N-terminal kinase; L-NAME, N ω -nitro-L-arginine methyl ester; LPS, Lipopolysaccharide; Ly6g/Gr1, Lymphocyte antigen 6 complex; M, Muscarinic; mAb, Monoclonal antibody; MAPKs, Mitogen-associated protein kinases; MBP, Major basic protein; mEARs, Mouse eosinophil associated ribonu- cleases; MHC, Major histocompatibility complex; mPT, Mitochondrial permeability transition; MyD88, Myeloid differentiation factor 88; NF, Nuclear factor; NK-1R, Neurokinin-1 receptor; nNOS, Neuronal nitric oxide synthase; NO, Nitric oxide; NO 2 - , Nitrate; OVA, Ovalbumin; PARP, Polymerase; PMN, Polymorphonuclear; RANTES, Regulated on activated, normal T cell expressed and secreted; RNases, Ribonucleases; ROS, Reactive oxidative species; Siglec, Sialic acid-binding immu- noglobulin-like lectin; Siglec-8, Sialic acid-binding immunoglobulin-like lec- tin humans; Siglec-F, Sialic acid-binding immunoglobulin-like lectin mice; SP, Substance P; SSC, Side scatter; ST2, Suppression of tumourigenicity 2 receptor; TFs, Transcription factors; TGF-β, Transforming growth factor-beta; Th, T-helper; TLR, Toll like-receptor; TNF-α, Tumour necrosis factor-alpha; TNFR, Tumour necrosis factor receptor; TPH, Tryptophan hydroxylase; TRPV1, Transient receptor potential vanilloid type-1; UC, Ulcerative colitis; vAChT, Vesicular acetylcholine transporter; VCAM, Vascular cell adhesion molecule doi: 10.1093/ibd/izz024 Published online 11 March 2019 © 2019 Crohn’s & Colitis Foundation. 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