Clinical and Translational Research
Copyright ©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Pathophysiol. Nov 22, 2021; 12(6): 115-133
Published online Nov 22, 2021. doi: 10.4291/wjgp.v12.i6.115
Chemokine receptor 8 expression may be linked to disease severity and elevated interleukin 6 secretion in acute pancreatitis
Mwangala Nalisa, Ekene Emmanuel Nweke, Martin D Smith, Jones Omoshoro-Jones, John WS Devar, Rebecca Metzger, Tanya N Augustine, Pascaline N Fru
Mwangala Nalisa, Ekene Emmanuel Nweke, Martin D Smith, Jones Omoshoro-Jones, John WS Devar, Pascaline N Fru, Department of Surgery, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2193, Gauteng, South Africa
Martin D Smith, Jones Omoshoro-Jones, John WS Devar, Department of Surgery, Chris Hani Baragwanath Academic Hospital, Johannesburg 1864, Gauteng, South Africa
Rebecca Metzger, Institut für Immunologie, Ludwig-Maximilians-Universität München, München 80539, Germany
Tanya N Augustine, School of Anatomical Sciences, Faculty of Health Science, University of the Witwatersrand, Johannesburg 2193, Gauteng, South Africa
Author contributions: Nalisa M, Nweke EE, Smith M, Augustine TN and Fru PN designed the research; Nalisa M, Nweke EE, Omoshoro-Jones J, Devar JWS, Metzger R and Fru PN performed the research; Nalisa M, Nweke EE, Smith M, Augustine TN, Metzger R and Fru PN contributed new reagents/analytic tools; Nalisa M, Nweke EE, Augustine TN and Fru PN wrote the paper; all authors analysed, interpreted the data and approved the final version.
Supported by the South African National Research Foundation, No. 121277; the University of the Witwatersrand Individual Research, No. 001283844110151211055142; and the Faculty of Health Sciences, University of the Witwatersrand Seed Funding, No. 0012518441101512110500000000000000004550.
Institutional review board statement: All procedures performed in this study involving human participants were in accordance with the ethical standards of the University of the Witwatersrand Human research ethics committee (M180133) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Conflict-of-interest statement: All authors have nothing to disclose
Data sharing statement: No additional data is available
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Pascaline N Fru, BSc, MSc, PhD, Senior Scientist, Department of Surgery, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, 7 York Road, Parktown, Johannesburg 2193, Gauteng, South Africa. pascaline.fru@wits.ac.za
Received: April 16, 2021
Peer-review started: April 16, 2021
First decision: June 23, 2021
Revised: July 8, 2021
Accepted: September 14, 2021
Article in press: September 14, 2021
Published online: November 22, 2021
Processing time: 213 Days and 16.1 Hours
Abstract
BACKGROUND

Acute pancreatitis (AP) is an inflammatory disease, which presents with epigastric pain and is clinically diagnosed by amylase and lipase three times the upper limit of normal. The 2012 Atlanta classification stratifies the severity of AP as one of three risk categories namely, mild AP (MAP), moderately severe AP (MSAP), and severe AP (SAP). Challenges in stratifying AP upon diagnosis suggest that a better understanding of the underlying complex pathophysiology may be beneficial.

AIM

To identify the role of the chemokine receptor 8 (CCR8), expressed by T-helper type-2 Lymphocytes and peritoneal macrophages, and its possible association to Interleukin (IL)-6 and AP stratification.

METHODS

This study was a prospective case-control study. A total of 40 patients were recruited from the Chris Hani Baragwanath Academic Hospital and the Charlotte Maxeke Johannesburg Academic Hospital. Bioassays were performed on 29 patients (14 MAP, 11 MSAP, and 4 SAP) and 6 healthy controls as part of a preliminary study. A total of 12 mL of blood samples were collected at Day (D) 1, 3, 5, and 7 post epigastric pain. Using multiplex immunoassay panels, real-time polymerase chain reaction (qRT-PCR) arrays, and multicolour flow cytometry analysis, immune response-related proteins, genes, and cells were profiled respectively. GraphPad Prism™ software and fold change (FC) analysis was used to determine differences between the groups. P<0.05 was considered significant.

RESULTS

The concentration of IL-6 was significantly different at D3 post epigastric pain in both the MAP group and MSAP group with P = 0.001 and P = 0.013 respectively, in a multiplex assay. When a FC of 2 was applied to identify differentially expressed genes using RT2 Profiler, CCR8 was shown to increase steadily with disease severity from MAP (1.33), MSAP (38.28) to SAP (1172.45) median FC. Further verification studies using RT-PCR showed fold change increases of CCR8 in MSAP and SAP ranging from 1000 to 1000000 times when represented as Log10, compared to healthy control respectively at D3. The findings also showed differing lymphocyte and monocyte cell frequency between the groups. With monocyte population frequency as high as 70% in MSAP at D3.

CONCLUSION

The higher levels of CCR8 and IL-6 in the severe patients and immune cell differences compared to MAP and controls provide an avenue for exploring AP stratification to improve management.

Keywords: Acute Pancreatitis; Severity; Stratification, Interleukin-6; Chemokine Receptor 8; Lymphocytes; Monocytes

Core Tip: Chemokine receptor 8 (CCR8) is a chemokine receptor that is highly expressed on monocytes and cells of T helper type-2 (Th2) lineage including innate lymphoid cells group 2 and 3 (ILC2 and 3). This study shows possible linkages between increasing CCR8 expression and severity in mainly moderately severe acute pancreatitis (MSAP) patients when compared to mild acute pancreatitis (MAP). Differing lymphocyte and monocyte cell frequencies suggest that in MAP, interleukin (IL)-6 was highly expressed in lymphocytes, and in the severe patients [MSAP and severe acute pancreatitis (SAP)] were highly expressed by monocytes. The findings open doors for future work, which could include an in-depth look at IL-6 producing cells such as Th2 Lymphocytes, monocytes, and innate ILC2 to determine cell-associated cytokine as a novel approach in prognosticating AP disease severity.