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Helminth 2-Cys peroxiredoxin drives Th2 responses through a mechanism involving alternatively activated macrophages

Sheila Donnelly^*, Colin M. Stack^*, Sandra M. O'Neill, Ahmed A. Sayed, David L. Williams and John P. Dalton^*,1

^* Institute for the Biotechnology of Infectious Diseases, University of Technology Sydney, Sydney, Australia;

School of Nursing, Dublin City University, Glasnevin, Dublin, Ireland; and

Department of Biological Sciences, Illinois State University, Normal, Illinois, USA

¹Correspondence: Level 6, Bldg. 4, University of Technology Sydney, Cnr. Thomas and Harris St., Ultimo, Sydney, NSW 2007, Australia. E-mail: john.dalton{at}uts.edu.au

During helminth infections, alternatively activated macrophages (AAMacs) are key to promoting Th2 responses and suppressing Th1-driven inflammatory pathology. Th2 cytokines IL-4 and/or IL-13 are believed to be important in the induction and activation of AAMacs. Using murine models for the helminth infections caused by Fasciola hepatica (Fh) and Schistosoma mansoni (Sm), we show that a secreted antioxidant, peroxiredoxin (Prx), induces alternative activation of macrophages. These activated, Ym1-expressing macrophages enhanced the secretion of IL-4, IL-5, and IL-13 from naive CD4⁺ T cells. Administration of recombinant FhPrx and SmPrx to wild-type and IL-4^–/– and IL-13^–/– mice induced the production of AAMacs. In addition, Prx stimulated the expression of markers of AAMacs (particularly, Ym1) in vitro, and therefore can act independently of IL-4/IL-13 signaling. The immunomodulatory property of Prx is not due to its antioxidant activity, as an inactive recombinant variant with active site Cys residues replaced by Gly could also induce AAMacs and Th2 responses. Immunization of mice with recombinant Prx or passive transfer of anti-Prx antibodies prior to infection with Fh not only blocked the induction of AAMacs but also the development of parasite-specific Th2 responses. We propose that Prx activates macrophages as an initial step in the induction of Th2 responses by helminth parasites and is thereby a novel pathogen-associated molecular pattern.—Donnelly, S., Stack, C. M., O'Neill, S. M., Sayed, A. A., Williams, D. L., Dalton, J. P. Helminth 2-Cys peroxiredoxin drives Th2 responses through a mechanism involving alternatively activated macrophages.

Key Words: antioxidant • immune modulation • innate immunity