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

PLoS Pathog. 2018 Mar 16;14(3):e1006949. doi: 10.1371/journal.ppat.1006949. eCollection 2018 Mar.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • Antineoplastic Agents
  • Ccr3 protein, mouse
  • Cytokines
  • Receptors, CCR3
  • Interleukin-4