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ACCUMULATION OF CXCL10-EXPRESSING CD163L1+ MACROPHAGES IN THE SIGMOID COLON OF DIVERTICULITIS PATIENTS
Kathleen M. Schieffer*1, Scott Emrich1, Gregory S. Yochum1,2, Walter Koltun1
1Surgery, Pennsylvania State University College of Medicine, Hershey, PA; 2Biochemistry & Molecular Biology, Pennsylvania State University College of Medicine, Hershey, PA
Introduction
Diverticulosis is an asymptomatic condition found primarily in the sigmoid colon of individuals living in Western countries. Diverticula are defined as herniations of mucosal and submucosal layers through the colonic wall. In about 4% of individuals, diverticular inflammation results in diverticulitis. A subset of these diverticulitis patients are refractory to therapy and require surgical intervention to resect the diseased sigmoid colon. Although traditionally thought to result from diverticular obstruction, recent data from our lab suggested that an altered immune state may contribute to diverticulitis. We found up-regulation of CD163L1, which encodes a scavenger receptor on intestinal macrophages, within diverticulitis tissue. The aim of this study was to investigate CD163L1+ macrophages and chemokine gene expression in surgically resected sigmoid colon tissues of control and diverticulitis patients.
Methods
Tissue was assessed from an uninvolved area adjacent to a region of the sigmoid colon chronically affected by diverticulitis. We performed Pearson correlation on transcripts associated with macrophage signaling identified by RNA-seq analysis. CD163L1 and C-X-C chemokine 10 (CXCL10) gene expression levels were confirmed in an independent cohort using reverse transcription and quantitative PCR. We used immunofluorescence microscopy to localize CD163L1+CD68+ macrophages and CXCL10 levels in intestinal tissue and enzyme linked immunosorbent assay to measure CXCL10 levels in patient sera.
Results
Correlation analysis of macrophage signaling transcripts identified two cellular phenotypes, an anti-inflammatory phenotype corresponding to a positive correlation between CD163, CD209, and interleukin 10 (IL10) and a pro-inflammatory phenotype identified by a positive correlation between CD163L1 and CXCL10. As our previous RNA-seq data suggested an enhanced immune response in diverticulitis patients, we confirmed that CD163L1 (P=0.039) and CXCL10 (P<0.001) gene expression was up-regulated in an independent cohort of diverticulitis and control sigmoid colon tissue. Correspondingly, we found an increased number of CD163L1+CD68+ macrophages in the sigmoid colon of diverticulitis patients relative to controls (P=0.036), of which those at the luminal surface of the crypt expressed the chemokine CXCL10. These diverticulitis patients also displayed heightened CXCL10 levels in their serum (P=0.011).
Conclusion
Diverticulitis patients requiring surgical intervention harbor increased levels of CD163L1+ macrophages in the colonic mucosa, of which a subset express the pro-inflammatory chemokine CXCL10. As CXCL10 functions as a chemoattractant for inflammatory cells, further studies are warranted to understand how CXCL10 contributes to diverticulitis and whether this chemokine can serve as a serum biomarker for disease onset or outcomes.
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