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

Research output: Contribution to journalArticle

Original languageEnglish
Article number e1006949
Number of pages20
JournalPLoS Pathogens
Volume14
Issue number3
Early online date16 Mar 2018
DOIs
DateAccepted/In press - 26 Feb 2018
DateE-pub ahead of print - 16 Mar 2018
DatePublished (current) - Mar 2018

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.

    Research areas

  • 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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    Rights statement: This is the final published version of the article (version of record). It first appeared online via PLoS at DOI: 10.1371/journal.ppat.1006949. Please refer to any applicable terms of use of the publisher.

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