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
ARTICLE HIGHLIGHTS
Research background

Chemokine receptor 8 (CCR8) is a chemokine receptor that is highly expressed on monocytes and cells of T helper type-2 Lineage including innate lymphoid cells group 2 and 3 (ILC2 and 3). Upregulation in more severe cases of acute pancreatitis (AP) may be linked to elevated levels of interleukin (IL)-6 and upregulation of CCR8.

Research motivation

There is currently no known treatment for AP and no clear early immune markers to effectively distinguish between moderately severe AP and severe AP. The complex underlying pathophysiology further complicates this, necessitating studies to better understand the ensuing immune responses for improved stratification.

Research objectives

To identify the role of the CCR8, expressed by Th2 Lymphocytes and peritoneal macrophages, and its possible association to IL-6 as early markers to assist with AP stratification.

Research methods

A total of 40 patients were recruited from the Chris Hani Baragwanath Hospital and the Charlotte Maxeke Johannesburg Academic Hospital in Johannesburg, South Africa. Bioassays were performed on 29 patients consisting of 14 mild AP (MAP), 11 moderately severe AP (MSAP), and 4 severe AP (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 (RT-PCR) arrays, and multicolour flow cytometry analysis, immune response-related proteins, genes, and cells were profiled respectively. The fold change (FC) analysis was used to determine differences between the groups.

Research results

This study shows possible linkages between increasing CCR8 expression and severity in mainly MSAP patients when compared to MAP. The concentration of IL-6 was significantly different at D3 post epigastric pain in both MAP group and MSAP group with P = 0.001 and P = 0.013 respectively, in a multiplex assay. CCR8 was shown to increase with severity with the following FC for MAP (1.33), MSAP (38.28) to SAP (1172.45). 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 controls respectively at Day 3 post epigastric pain.

Research conclusions

Notable increases in CCR8 and IL-6 in severe patients were observed. Lymphocyte and monocyte cell frequencies suggest that in MAP, IL-6 was highly expressed in lymphocytes, and the severe patients (MSAP and SAP) were highly expressed by monocytes. This provides an avenue for exploring AP stratification to improve management.

Research perspectives

There is an opportunity to further investigate IL-6 producing cells such as T helper 2 lymphocytes, monocytes, and innate lymphoid cells group 2 and associated CCR8 increases, to determine cell-associated cytokine as a novel approach for AP risk stratification.