CCL28 modulates neutrophil responses during infection with mucosal pathogens

  1. Gregory T Walker
  2. Araceli Perez-Lopez
  3. Steven Silva
  4. Michael H Lee
  5. Elisabet Bjånes
  6. Nicholas Dillon
  7. Stephanie L Brandt
  8. Romana R Gerner
  9. Karine Melchior
  10. Grant J Norton
  11. Felix A Argueta
  12. Frenchesca Dela Pena
  13. Lauren Park
  14. Victor A Sosa-Hernandez
  15. Rodrigo Cervantes-Diaz
  16. Sandra Romero-Ramirez
  17. Monica Cartelle Gestal
  18. Jose L Maravillas-Montero
  19. Sean-Paul Nuccio
  20. Victor Nizet
  21. Manuela Raffatellu  Is a corresponding author
  1. University of California, San Diego, United States
  2. National Autonomous University of Mexico, Mexico
  3. The University of Texas at Dallas, United States
  4. Technical University of Munich, Germany
  5. Louisiana State University in Shreveport, United States

Abstract

The chemokine CCL28 is highly expressed in mucosal tissues, but its role during infection is not well understood. Here we show that CCL28 promotes neutrophil accumulation in the gut of mice infected with Salmonella and in the lung of mice infected with Acinetobacter. Neutrophils isolated from the infected mucosa expressed the CCL28 receptors CCR3 and, to a lesser extent, CCR10, on their surface. The functional consequences of CCL28 deficiency varied between the two infections: Ccl28-/- mice were highly susceptible to Salmonella gut infection but highly resistant to otherwise lethal Acinetobacter lung infection. In vitro, unstimulated neutrophils harbored pre-formed intracellular CCR3 that was rapidly mobilized to the cell surface following phagocytosis or inflammatory stimuli. Moreover, CCL28 stimulation enhanced neutrophil antimicrobial activity, production of reactive oxygen species, and formation of extracellular traps, all processes largely dependent on CCR3. Consistent with the different outcomes in the two infection models, neutrophil stimulation with CCL28 boosted the killing of Salmonella but not Acinetobacter. CCL28 thus plays a critical role in the immune response to mucosal pathogens by increasing neutrophil accumulation and activation, which can enhance pathogen clearance but also exacerbate disease depending on the mucosal site and the infectious agent.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. Raw data are available at Dryad.

The following data sets were generated
    1. Raffatellu M
    (2024) CCL28 Manuscript Source Data File
    Dryad Digital Repository, doi:10.5061/dryad.59zw3r2j6.

Article and author information

Author details

  1. Gregory T Walker

    Department of Pediatrics, University of California, San Diego, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Araceli Perez-Lopez

    Biomedicine Research Unit, National Autonomous University of Mexico, Mexico City, Mexico
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5399-1958
  3. Steven Silva

    Department of Pediatrics, University of California, San Diego, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Michael H Lee

    Department of Pediatrics, University of California, San Diego, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Elisabet Bjånes

    Department of Pediatrics, University of California, San Diego, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Nicholas Dillon

    Department of Biological Sciences, The University of Texas at Dallas, Richardson, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Stephanie L Brandt

    Department of Pediatrics, University of California, San Diego, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Romana R Gerner

    School of Life Sciences, Technical University of Munich, Munich, Germany
    Competing interests
    The authors declare that no competing interests exist.
  9. Karine Melchior

    Department of Pediatrics, University of California, San Diego, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Grant J Norton

    Department of Pediatrics, University of California, San Diego, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Felix A Argueta

    Department of Pediatrics, University of California, San Diego, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Frenchesca Dela Pena

    Department of Pediatrics, University of California, San Diego, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Lauren Park

    Department of Pediatrics, University of California, San Diego, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Victor A Sosa-Hernandez

    Research Support Network, National Autonomous University of Mexico, Mexico City, Mexico
    Competing interests
    The authors declare that no competing interests exist.
  15. Rodrigo Cervantes-Diaz

    Research Support Network, National Autonomous University of Mexico, Mexico City, Mexico
    Competing interests
    The authors declare that no competing interests exist.
  16. Sandra Romero-Ramirez

    Research Support Network, National Autonomous University of Mexico, Mexico City, Mexico
    Competing interests
    The authors declare that no competing interests exist.
  17. Monica Cartelle Gestal

    Department of Microbiology and Immunology, Louisiana State University in Shreveport, Shreveport, United States
    Competing interests
    The authors declare that no competing interests exist.
  18. Jose L Maravillas-Montero

    Research Support Network, National Autonomous University of Mexico, Mexico City, Mexico
    Competing interests
    The authors declare that no competing interests exist.
  19. Sean-Paul Nuccio

    Department of Pediatrics, University of California, San Diego, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9683-9278
  20. Victor Nizet

    Department of Pediatrics, University of California, San Diego, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3847-0422
  21. Manuela Raffatellu

    Department of Pediatrics, University of California, San Diego, La Jolla, United States
    For correspondence
    manuelar@ucsd.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6487-4215

Funding

National Institute of Allergy and Infectious Diseases (AI121928)

  • Manuela Raffatellu

Japan Agency for Medical Research and Development (JP233fa627003)

  • Manuela Raffatellu

Burroughs Wellcome Fund

  • Manuela Raffatellu

National Institute of Diabetes and Digestive and Kidney Diseases (DK120515)

  • Manuela Raffatellu

National Institute of Allergy and Infectious Diseases (Mucosal Immunology Studies Team)

  • Araceli Perez-Lopez

Crohn's and Colitis Foundation (649744)

  • Romana R Gerner

National Institute of Diabetes and Digestive and Kidney Diseases (DK007202)

  • Michael H Lee

National Institute of Allergy and Infectious Diseases (AI169989)

  • Michael H Lee

Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD087978)

  • Nicholas Dillon

National Institute of Allergy and Infectious Diseases (AI124316)

  • Nicholas Dillon
  • Victor Nizet

National Institute of Allergy and Infectious Diseases (AI007036)

  • Gregory T Walker

National Institute of Allergy and Infectious Diseases (AI145325)

  • Victor Nizet

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All mouse experiments were reviewed and approved by the Institutional Animal Care and Use Committees at UC Irvine (protocol #2009-2885) and UC San Diego (protocols #S17107 and #S00227M).

Human subjects: Whole-blood samples were collected from healthy donors recruited at a tertiary care center in Mexico City (Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán). Healthy donors signed an informed consent form before inclusion in the study, and the protocol was approved by the Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán ethics and research committees (Ref. 3341) in compliance with the Helsinki declaration.

Copyright

© 2024, Walker et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Gregory T Walker
  2. Araceli Perez-Lopez
  3. Steven Silva
  4. Michael H Lee
  5. Elisabet Bjånes
  6. Nicholas Dillon
  7. Stephanie L Brandt
  8. Romana R Gerner
  9. Karine Melchior
  10. Grant J Norton
  11. Felix A Argueta
  12. Frenchesca Dela Pena
  13. Lauren Park
  14. Victor A Sosa-Hernandez
  15. Rodrigo Cervantes-Diaz
  16. Sandra Romero-Ramirez
  17. Monica Cartelle Gestal
  18. Jose L Maravillas-Montero
  19. Sean-Paul Nuccio
  20. Victor Nizet
  21. Manuela Raffatellu
(2024)
CCL28 modulates neutrophil responses during infection with mucosal pathogens
eLife 13:e78206.
https://doi.org/10.7554/eLife.78206

Share this article

https://doi.org/10.7554/eLife.78206

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