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.
Highlights
Infections by helminth parasites are frequently accompanied by overt eosinophilia at parasitized tissue niches[1]
We define a cellular mechanism whereby the interlukin-4 dependent activation of tissue macrophages are essential to sustain the recruitment of larvicidal eosinophil
CCR3-dependent tissue eosinophilia is necessary for immunity to B. malayi invading larvae
Summary
Infections by helminth parasites are frequently accompanied by overt eosinophilia at parasitized tissue niches[1]. Antibody-dependent cellular cytotoxicity (ADCC) and granule-released products have been implicated as the mechanism by which eosinophils mediate parasite helminth larval attrition both in vitro[11, 12] and in vivo[4, 7, 8]. Corroborating eosinophilic immunity demonstrable in rodent models, clinical studies have identified that interleukin-5, a growth factor supporting eosinophilia, is a correlate of resistance to helminth re-infection[13, 14]. Whilst the importance of eosinophils in immunity to tissueinvading helminth parasites is well-defined, much less is understood about the cellular mechanism by which a tissue eosinophilia in parasitized tissues is coordinated and maintained
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