Antibodies Trap Tissue Migrating Helminth Larvae and Prevent Tissue Damage by Driving IL-4Rα-Independent Alternative Differentiation of Macrophages

Julia Esser-von Bieren, Ilaria Mosconi, Romain Guiet, Alessandra Piersgilli, Beatrice Volpe, Fei Chen, William C. Gause, Arne Seitz, J. Sjef Verbeek, Nicola L. Harris

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Abstract

Approximately one-third of the world's population suffers from chronic helminth infections with no effective vaccines currently available. Antibodies and alternatively activated macrophages (AAM) form crucial components of protective immunity against challenge infections with intestinal helminths. However, the mechanisms by which antibodies target these large multi-cellular parasites remain obscure. Alternative activation of macrophages during helminth infection has been linked to signaling through the IL-4 receptor alpha chain (IL-4Rα), but the potential effects of antibodies on macrophage differentiation have not been explored. We demonstrate that helminth-specific antibodies induce the rapid trapping of tissue migrating helminth larvae and prevent tissue necrosis following challenge infection with the natural murine parasite Heligmosomoides polygyrus bakeri (Hp). Mice lacking antibodies (JH-/-) or activating Fc receptors (FcRγ-/-) harbored highly motile larvae, developed extensive tissue damage and accumulated less Arginase-1 expressing macrophages around the larvae. Moreover, Hp-specific antibodies induced FcRγ- and complement-dependent adherence of macrophages to larvae in vitro, resulting in complete larval immobilization. Antibodies together with helminth larvae reprogrammed macrophages to express wound-healing associated genes, including Arginase-1, and the Arginase-1 product L-ornithine directly impaired larval motility. Antibody-induced expression of Arginase-1 in vitro and in vivo occurred independently of IL-4Rα signaling. In summary, we present a novel IL-4Rα-independent mechanism of alternative macrophage activation that is antibody-dependent and which both mediates anti-helminth immunity and prevents tissue disruption caused by migrating larvae.

Original languageEnglish
Article numbere1003771
Number of pages15
JournalPLoS Pathogens
Volume9
Issue number11
DOIs
Publication statusPublished - 1 Nov 2013
Externally publishedYes

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