CCL28 modulates neutrophil responses during infection with mucosal pathogens
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.
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CCL28 Manuscript Source Data FileDryad Digital Repository, doi:10.5061/dryad.59zw3r2j6.
Article and author information
Author details
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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