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©The Author(s) 2018. Published by Baishideng Publishing Group Inc. All rights reserved.
Temporal clinical, proteomic, histological and cellular immune responses of dextran sulfate sodium-induced acute colitis
Natalia Schneider Nunes, Saejeong Kim, Maggie Sundby, Parwathy Chandran, Scott Robert Burks, Ana Helena Paz, Joseph Alan Frank
Natalia Schneider Nunes, Saejeong Kim, Maggie Sundby, Parwathy Chandran, Scott Robert Burks, Joseph Alan Frank, Frank Laboratory, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, MD 20892, United States
Natalia Schneider Nunes, Ana Helena Paz, Gastroenterology and Hepatology Sciences Graduate Program, Universidade Federal do Rio Grande do Sul, Porto Alegre 90035-093, Brazil
Joseph Alan Frank, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, MD 20892, United States
Author contributions: Nunes NS, Paz AH and Frank JA assisted in research design; Nunes NS carried out the research; Nunes NS and Frank JA analyzed data and wrote manuscript; Sundby M and Paz AH assisted with histological analysis; Kim S and Chandran P assisted with flow cytometry analysis; Burks SR assisted with proteomic analysis; all authors reviewed and approved manuscript.
Institutional animal care and use committee statement: All procedures involving animal subjects were reviewed and approved by the Animal Care and Use Committee of the Clinical Center at the National Institutes of Health (ACUC protocol number: LDRR16-02).
Conflict-of-interest statement: The authors declare that they have no conflict-of-interests.
Data sharing statement: Materials used for the current study are available from the corresponding author on reasonable request.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (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/
Correspondence to: Natalia S Nunes, PhD, Frank Laboratory, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bldg 10 Room B1N256, 10 Center Drive, Bethesda, MD 20892, United States. natalia.schneidernunes@nih.gov
Telephone: +1-301-9063353
Received: June 21, 2018
Peer-review started: June 21, 2018
First decision: August 1, 2018
Revised: August 6, 2018
Accepted: August 24, 2018
Article in press: August 24, 2018
Published online: October 14, 2018
AIM
To investigate the temporal clinical, proteomic, histological and cellular immune profiles of dextran sulfate sodium (DSS)-induced acute colitis.
METHODS
Acute colitis was induced in C57Bl/6 female mice by administration of 1%, 2% or 3% DSS in drinking water for 7 d. Animals were monitored daily for weight loss, stool consistency and blood in the stool, while spleens and colons were harvested on day 8. A time course analysis was performed in mice ingesting 3% DSS, which included colon proteomics through multiplex assay, colon histological scoring by a blinded investigator, and immune response through flow cytometry or immunohistochemistry of the spleen, mesenteric lymph node and colon.
RESULTS
Progressive worsening of clinical colitis was observed with increasing DSS from 1% to 3%. In mice ingesting 3% DSS, colon shortening and increase in pro-inflammatory factors starting at day 3 was observed, with increased spleen weights at day 6 and day 8. This coincided with cellular infiltration in the colon from day 2 to day 8, with progressive accumulation of macrophages F4/80+, T helper CD4+ (Th), T cytotoxic CD8+ (Tcyt) and T regulatory CD25+ (Treg) cells, and progressive changes in colonic pathology including destruction of crypts, loss of goblet cells and depletion of the epithelial barrier. Starting on day 4, mesenteric lymph node and/or spleen presented with lower levels of Treg, Th and Tcyt cells, suggesting an immune cell tropism to the gut.
CONCLUSION
These results demonstrate that the severity of experimental colitis is dependent on DSS concentration, correlated with clinical, proteomic, histological and cellular immune response on 3% DSS.
Core tip: Our study contributes to a better understanding of the dextran sulfate sodium (DSS) acute colitis model in order to provide a stronger basis for novel therapies. Colonic proteomic temporal analysis reveals an increase in cytokines with a strong influx of immune cells. The highest cytokine levels were observed when animals were no longer drinking DSS, suggesting a rebound response. Secondary lymphoid organs contribute by sending different immune cells to the colon during the acute phase, such as CD4+, CD8+ and CD25+ T cells. Our results demonstrate involvement of the adaptive and innate immune responses during the acute phase of DSS-induced colitis.
