Antibodies trap tissue migrating helminth larvae and prevent tissue damage by driving IL-4Rα-independent alternative differentiation of macrophages

PLoS Pathog. 2013;9(11):e1003771. doi: 10.1371/journal.ppat.1003771. Epub 2013 Nov 14.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Helminth / genetics
  • Antibodies, Helminth / immunology*
  • Arginase / genetics
  • Arginase / immunology
  • Cell Differentiation / genetics
  • Cell Differentiation / immunology*
  • Gene Expression Regulation, Enzymologic / genetics
  • Gene Expression Regulation, Enzymologic / immunology
  • Larva
  • Macrophages / immunology*
  • Mice
  • Mice, Knockout
  • Nematospiroides dubius / immunology*
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / immunology*
  • Signal Transduction / genetics
  • Signal Transduction / immunology
  • Strongylida Infections / genetics
  • Strongylida Infections / immunology*

Substances

  • Antibodies, Helminth
  • Il4ra protein, mouse
  • Receptors, Cell Surface
  • Arg1 protein, mouse
  • Arginase

Grant support

This project was supported by the Swiss National Science Foundation (310030_133104). http://www.snf.ch/E/Pages/default.aspx NLH is additionally supported by the Swiss Vaccine Research Institute. http://www.swissvaccineresearchinstitute.ch/ The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.