Anatomical Variation in Mesenteric Macrophage Phenotypes in Crohn's Disease

Abstract

INTRODUCTION: Clinical trials are currently investigating whether an extended mesenteric resection for ileocecal resections could reduce postoperative recurrence in Crohn's disease. Resection of the mesorectum, which contains proinflammatory macrophages, during proct(ocol)ectomy, is associated with reduced recurrent inflammation and improved wound healing. We aimed to characterize the macrophages in the ileocecal mesentery, which were compared with those in the mesorectum, to provide a biological rationale for the ongoing trials. METHODS: In 13 patients with Crohn's disease and 4 control patients undergoing a proctectomy, tissue specimens were sampled at 3 locations from the mesorectum: distal (rectum), middle, and proximal (sigmoid). In 38 patients with Crohn's disease and 7 control patients undergoing ileocecal resections, tissue specimens also obtained from 3 locations: adjacent to the inflamed terminal ileum, adjacent to the noninflamed ileal resection margin, and centrally along the ileocolic artery. Immune cells from these tissue specimens were analyzed by flow cytometry for expression of CD206 to determine their inflammatory status. RESULTS: In the mesorectum, a gradient from proinflammatory to regulatory macrophages from distal to proximal was observed, corresponding to the adjacent inflammation of the intestine. By contrast, the ileocecal mesentery did not contain high amounts of proinflammatory macrophages adjacent to the inflamed tissue, and a gradient toward a more proinflammatory phenotype was seen in the central mesenteric area. DISCUSSION: Although the mesentery is a continuous structure, the mesorectum and the ileocecal mesentery show different immunological characteristics. Therefore, currently, there is no basis to perform an extended ileocecal resection in patients with Crohn's disease.

Improved diagnosis of inflammatory bowel disease and prediction and monitoring of response to anti-TNF alpha treatment based on measurement of signal transduction pathway activity

“…Our results support the increasing evidence that the pathogenesis (or mechanism of disease) of ileal IBD is distinct from colon-located IBD (Pierre et al, 2020), (Naftali et al, 2016), (Kredel et al, 2019), (Howell et al, 2018), (Meinzer et al, 2005), (Wu et al, 2010), (van der Meer et al, 2020. Interferons are activators of the JAK-STAT1/ 2 pathway which was in our analysis identified as specifically active in ileal CD (Platanias, 2005).…”

Improved diagnosis of inflammatory bowel disease and prediction and monitoring of response to anti-TNF alpha treatment based on measurement of signal transduction pathway activity

“…Our results support the increasing evidence that the pathogenesis (or mechanism of disease ) of ileal IBD is distinct from colon-located IBD 35 , 36 , 37 , 38 , 39 , 40 , 41 . Interferons are activators of the JAK-STAT1/2 pathway which was in our analysis identified as specifically active in ileal CD 42 .…”

Role of the Mesentery in Crohn's Terminal Ileitis

“…Notably, the opposite was found in the central ileal region of the mesentery, where the macrophages were strongly skewed toward a pro-inflammatory phenotype. 14 This gradient of the macrophage phenotype from pro-inflammatory in the proximal central mesentery to a regulatory phenotype in the more distal mesentery around the affected bowel contrasted with findings in the mesorectum where a gradient from proinflammatory to regulatory phenotype was observed in mesentery adjacent the rectum. 15 These findings are supported by observations related to the expression of the tissue remodeling macrophage marker “CD163,” in the mesenteric macrophages.…”