Interleukin-4 activated macrophages mediate immunity to filarial helminth infection by sustaining CCR3-dependent eosinophilia

Joseph D Turner, Nicolas Pionnier, Julio Furlong-Silva, Hanna Sjoberg, Stephen Cross, Alice Halliday, Ana F Guimaraes, Darren A N Cook, Andrew Steven, Nico Van Rooijen, Judith E Allen

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Abstract

Eosinophils are effectors in immunity to tissue helminths but also induce allergic immunopathology. Mechanisms of eosinophilia in non-mucosal tissues during infection remain unresolved. Here we identify a pivotal function of tissue macrophages (Mϕ) in eosinophil anti-helminth immunity using a BALB/c mouse intra-peritoneal Brugia malayi filarial infection model. Eosinophilia, via C-C motif chemokine receptor (CCR)3, was necessary for immunity as CCR3 and eosinophil impairments rendered mice susceptible to chronic filarial infection. Post-infection, peritoneal Mϕ populations proliferated and became alternatively-activated (AAMϕ). Filarial AAMϕ development required adaptive immunity and interleukin-4 receptor-alpha. Depletion of Mϕ prior to infection suppressed eosinophilia and facilitated worm survival. Add back of filarial AAMϕ in Mϕ-depleted mice recapitulated a vigorous eosinophilia. Transfer of filarial AAMϕ into Severe-Combined Immune Deficient mice mediated immunological resistance in an eosinophil-dependent manner. Exogenous IL-4 delivery recapitulated tissue AAMϕ expansions, sustained eosinophilia and mediated immunological resistance in Mϕ-intact SCID mice. Co-culturing Brugia with filarial AAMϕ and/or filarial-recruited eosinophils confirmed eosinophils as the larvicidal cell type. Our data demonstrates that IL-4/IL-4Rα activated AAMϕ orchestrate eosinophil immunity to filarial tissue helminth infection.
Original languageEnglish
Article number e1006949
Number of pages20
JournalPLoS Pathogens
Volume14
Issue number3
Early online date16 Mar 2018
DOIs
Publication statusPublished - Mar 2018

Keywords

  • Animals
  • Antineoplastic Agents/pharmacology
  • Brugia malayi/drug effects
  • Cytokines/genetics
  • Eosinophilia/drug therapy
  • Female
  • Filariasis/drug therapy
  • Interleukin-4/pharmacology
  • Macrophages/drug effects
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, SCID
  • Receptors, CCR3/genetics

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  • Cite this

    Turner, J. D., Pionnier, N., Furlong-Silva, J., Sjoberg, H., Cross, S., Halliday, A., Guimaraes, A. F., Cook, D. A. N., Steven, A., Van Rooijen, N., & Allen, J. E. (2018). Interleukin-4 activated macrophages mediate immunity to filarial helminth infection by sustaining CCR3-dependent eosinophilia. PLoS Pathogens, 14(3), [ e1006949]. https://doi.org/10.1371/journal.ppat.1006949, https://doi.org/10.1371/journal.ppat.1006949