Skip to main content

Main menu

  • Home
  • Articles
    • Current Issue
    • Next in The JI
    • Archive
    • Brief Reviews
    • Pillars of Immunology
    • Translating Immunology
    • Most Read
    • Top Downloads
    • Annual Meeting Abstracts
  • COVID-19/SARS/MERS Articles
  • Info
    • About the Journal
    • For Authors
    • Journal Policies
    • Influence Statement
    • For Advertisers
  • Editors
  • Submit
    • Submit a Manuscript
    • Instructions for Authors
    • Journal Policies
  • Subscribe
    • Journal Subscriptions
    • Email Alerts
    • RSS Feeds
    • ImmunoCasts
  • More
    • Most Read
    • Most Cited
    • ImmunoCasts
    • AAI Disclaimer
    • Feedback
    • Help
    • Accessibility Statement
  • Other Publications
    • American Association of Immunologists
    • ImmunoHorizons

User menu

  • Subscribe
  • Log in

Search

  • Advanced search
The Journal of Immunology
  • Other Publications
    • American Association of Immunologists
    • ImmunoHorizons
  • Subscribe
  • Log in
The Journal of Immunology

Advanced Search

  • Home
  • Articles
    • Current Issue
    • Next in The JI
    • Archive
    • Brief Reviews
    • Pillars of Immunology
    • Translating Immunology
    • Most Read
    • Top Downloads
    • Annual Meeting Abstracts
  • COVID-19/SARS/MERS Articles
  • Info
    • About the Journal
    • For Authors
    • Journal Policies
    • Influence Statement
    • For Advertisers
  • Editors
  • Submit
    • Submit a Manuscript
    • Instructions for Authors
    • Journal Policies
  • Subscribe
    • Journal Subscriptions
    • Email Alerts
    • RSS Feeds
    • ImmunoCasts
  • More
    • Most Read
    • Most Cited
    • ImmunoCasts
    • AAI Disclaimer
    • Feedback
    • Help
    • Accessibility Statement
  • Follow The Journal of Immunology on Twitter
  • Follow The Journal of Immunology on RSS

The Wnt–β-Catenin–IL-10 Signaling Axis in Intestinal APCs Protects Mice from Colitis-Associated Colon Cancer in Response to Gut Microbiota

Daniel Swafford, Arulkumaran Shanmugam, Punithavathi Ranganathan, Indumathi Manoharan, Mohamed S. Hussein, Nikhil Patel, Humberto Sifuentes, Pandelakis A. Koni, Puttur D. Prasad, Muthusamy Thangaraju and Santhakumar Manicassamy
J Immunol October 15, 2020, 205 (8) 2265-2275; DOI: https://doi.org/10.4049/jimmunol.1901376
Daniel Swafford
*Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA 30912;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Arulkumaran Shanmugam
*Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA 30912;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Punithavathi Ranganathan
*Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA 30912;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Indumathi Manoharan
*Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA 30912;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Mohamed S. Hussein
*Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA 30912;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Mohamed S. Hussein
Nikhil Patel
†Department of Pathology, Medical College of Georgia, Augusta University, Augusta, GA 30912;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Nikhil Patel
Humberto Sifuentes
‡Department of Medicine, Medical College of Georgia, Augusta University, Augusta, GA 30912;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Pandelakis A. Koni
§Parker Institute for Cancer Immunotherapy, San Francisco, CA 94129; and
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Pandelakis A. Koni
Puttur D. Prasad
¶Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA 30912
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Puttur D. Prasad
Muthusamy Thangaraju
¶Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA 30912
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Santhakumar Manicassamy
*Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA 30912;
‡Department of Medicine, Medical College of Georgia, Augusta University, Augusta, GA 30912;
¶Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA 30912
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Santhakumar Manicassamy
  • Article
  • Figures & Data
  • Info & Metrics
  • PDF + SI
  • PDF
Loading

Key Points

  • The canonical Wnt pathway in intestinal APCs protects against CAC.

  • LRP5/6–β-catenin–IL-10 signaling in APCs suppresses chronic intestinal inflammation.

  • This pathway plays an important role in regulating intestinal commensal homeostasis.

Abstract

Loss of immune tolerance to gut microflora is inextricably linked to chronic intestinal inflammation and colitis-associated colorectal cancer (CAC). The LRP5/6 signaling cascade in APCs contributes to immune homeostasis in the gut, but whether this pathway in APCs protects against CAC is not known. In the current study, using a mouse model of CAC, we show that the LRP5/6–β-catenin–IL-10 signaling axis in intestinal CD11c+ APCs protects mice from CAC by regulating the expression of tumor-promoting inflammatory factors in response to commensal flora. Genetic deletion of LRP5/6 in CD11c+ APCs in mice (LRP5/6ΔCD11c) resulted in enhanced susceptibility to CAC. This is due to a microbiota-dependent increased expression of proinflammatory factors and decreased expression of the immunosuppressive cytokine IL-10. This condition could be improved in LRP5/6ΔCD11c mice by depleting the gut flora, indicating the importance of LRP5/6 in mediating immune tolerance to the gut flora. Moreover, mechanistic studies show that LRP5/6 suppresses the expression of tumor-promoting inflammatory factors in CD11c+ APCs via the β-catenin–IL-10 axis. Accordingly, conditional activation of β-catenin specifically in CD11c+ APCs or in vivo administration of IL-10 protected LRP5/6ΔCD11c mice from CAC by suppressing the expression of inflammatory factors. In summary, in this study, we identify a key role for the LRP5/6–β-catenin–IL-10 signaling pathway in intestinal APCs in resolving chronic intestinal inflammation and protecting against CAC in response to the commensal flora.

Footnotes

  • This work was supported by National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases Awards DK097271 and DK123360 and Augusta University Awards IGPB0003 and ESA00041 to S.M.

  • The online version of this article contains supplemental material.

  • Abbreviations used in this article:

    AOM
    azoxymethane
    AU
    Augusta University
    CAC
    colitis-associated CRC
    CA-βcat
    constitutively active β-catenin
    CD
    Crohn's disease
    CRC
    colorectal cancer
    DC
    dendritic cell
    DN-βcat
    dominant-negative β-catenin
    DSS
    dextran sodium sulfate
    FMT
    fecal microbiota transplantation
    IBD
    inflammatory bowel disease
    LP
    lamina propria
    qPCR
    quantitative PCR
    SFB
    segmented filamentous bacteria
    SOCS
    suppressor of cytokine signaling
    Tr1
    type 1 Treg
    Treg
    regulatory T cell
    UC
    ulcerative colitis
    WT
    wild type.

  • Received November 18, 2019.
  • Accepted August 17, 2020.
  • Copyright © 2020 by The American Association of Immunologists, Inc.
View Full Text

Pay Per Article - You may access this article (from the computer you are currently using) for 1 day for US$37.50

Regain Access - You can regain access to a recent Pay per Article purchase if your access period has not yet expired.

Log in using your username and password

Forgot your user name or password?
PreviousNext
Back to top

In this issue

The Journal of Immunology: 205 (8)
The Journal of Immunology
Vol. 205, Issue 8
15 Oct 2020
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Back Matter (PDF)
  • Editorial Board (PDF)
  • Front Matter (PDF)
Print
Download PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for your interest in spreading the word about The Journal of Immunology.

NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

Enter multiple addresses on separate lines or separate them with commas.
The Wnt–β-Catenin–IL-10 Signaling Axis in Intestinal APCs Protects Mice from Colitis-Associated Colon Cancer in Response to Gut Microbiota
(Your Name) has forwarded a page to you from The Journal of Immunology
(Your Name) thought you would like to see this page from the The Journal of Immunology web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
The Wnt–β-Catenin–IL-10 Signaling Axis in Intestinal APCs Protects Mice from Colitis-Associated Colon Cancer in Response to Gut Microbiota
Daniel Swafford, Arulkumaran Shanmugam, Punithavathi Ranganathan, Indumathi Manoharan, Mohamed S. Hussein, Nikhil Patel, Humberto Sifuentes, Pandelakis A. Koni, Puttur D. Prasad, Muthusamy Thangaraju, Santhakumar Manicassamy
The Journal of Immunology October 15, 2020, 205 (8) 2265-2275; DOI: 10.4049/jimmunol.1901376

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Share
The Wnt–β-Catenin–IL-10 Signaling Axis in Intestinal APCs Protects Mice from Colitis-Associated Colon Cancer in Response to Gut Microbiota
Daniel Swafford, Arulkumaran Shanmugam, Punithavathi Ranganathan, Indumathi Manoharan, Mohamed S. Hussein, Nikhil Patel, Humberto Sifuentes, Pandelakis A. Koni, Puttur D. Prasad, Muthusamy Thangaraju, Santhakumar Manicassamy
The Journal of Immunology October 15, 2020, 205 (8) 2265-2275; DOI: 10.4049/jimmunol.1901376
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like

Jump to section

  • Article
    • Abstract
    • Introduction
    • Materials and Methods
    • Results
    • Discussion
    • Disclosures
    • Acknowledgments
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • PDF + SI
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Identification and Characterization of Zebrafish Tlr4 Coreceptor Md-2
  • Activated Neutrophils Propagate Fetal Membrane Inflammation and Weakening through ERK and Neutrophil Extracellular Trap–Induced TLR-9 Signaling
  • Enhanced Proliferation of Ly6C+ Monocytes/Macrophages Contributes to Chronic Inflammation in Skin Wounds of Diabetic Mice
Show more INNATE IMMUNITY AND INFLAMMATION

Similar Articles

Navigate

  • Home
  • Current Issue
  • Next in The JI
  • Archive
  • Brief Reviews
  • Pillars of Immunology
  • Translating Immunology

For Authors

  • Submit a Manuscript
  • Instructions for Authors
  • About the Journal
  • Journal Policies
  • Editors

General Information

  • Advertisers
  • Subscribers
  • Rights and Permissions
  • Accessibility Statement
  • Public Access
  • Privacy Policy
  • Disclaimer

Journal Services

  • Email Alerts
  • RSS Feeds
  • ImmunoCasts
  • Twitter

Copyright © 2021 by The American Association of Immunologists, Inc.

Print ISSN 0022-1767        Online ISSN 1550-6606