Targeting eotaxin‐1 and CCR 3 receptor alleviates enteric neuropathy and colonic dysfunction in TNBS ‐induced colitis in guinea pigs

• Published in: Neurogastroenterology and motility Vol. 30; no. 11
• Main Authors: Filippone, R. T., Robinson, A. M., Jovanovska, V., Stavely, R., Apostolopoulos, V., Bornstein, J. C., Nurgali, K.
• Format: Journal Article
• Language: English
• Published: 01.11.2018
• ISSN: 1350-1925; 1365-2982
• DOI: 10.1111/nmo.13391

Abstract Background The accumulation of eosinophils is mediated by the chemokine receptor‐3 ( CCR 3)‐eotaxin axis. Increased expression of eotaxin and its receptor is associated with inflammatory bowel disease ( IBD ). Activation of eosinophils causes the release of cationic proteins that are neurotoxic such as eosinophil‐derived neurotoxin ( EDN ). Damage to enteric neurons alters neurally controlled functions of the gut correlated with intestinal inflammation. We hypothesized that inhibition of the CCR 3‐eotaxin axis will prevent inflammation‐induced functional changes to the gastrointestinal tract. Methods Hartley guinea pigs were administered with trinitrobenzene sulfonate ( TNBS ; 30 mg/kg in 30% ethanol) intrarectally to induce colitis. A CCR 3 receptor antagonist ( SB 328437 [ SB 3]) was injected intraperitoneally 1 hour postinduction of colitis. Animals were euthanized 7 days post‐treatment and colon tissues were collected for ex vivo studies. The EDN ‐positive eosinophils in the colon, indicating eosinophil activation, were quantified by immunohistochemistry. Effects of SB 3 treatment on gross morphological damage, enteric neuropathy, and colonic dysmotility were determined by histology, immunohistochemistry, and organ bath experiments. Key Results The number of EDN ‐positive eosinophils was significantly increased in the lamina propria in close proximity to myenteric ganglia in inflamed colon. The TNBS ‐induced inflammation caused significant damage to colonic architecture and inhibition of colonic motility. Treatment with SB 3 antagonist attenuated inflammation‐associated morphological damage in the colon, reduced infiltration of EDN ‐positive eosinophils and restored colonic motility to levels comparable to control and sham‐treated guinea pigs. Conclusion & Inferences This is the first study demonstrating that inhibition of CCR 3‐eotaxin axis alleviates enteric neuropathy and restores functional changes in the gut associated with TNBS ‐induced colitis.