Alternatively Activated Macrophages Elicited by Helminth Infection Can Be Reprogrammed to Enable Microbial Killing

Katie J Mylonas, Meera G Nair, Lidia Prieto-Lafuente, Daniel Paape, Judith E Allen

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

The prime function of classically activated macrophages (activated by Th1-type signals, such as IFN-gamma) is microbial destruction. Alternatively activated macrophages (activated by Th2 cytokines, such as IL-4 and IL-13) play important roles in allergy and responses to helminth infection. We utilize a murine model of filarial infection, in which adult nematodes are surgically implanted into the peritoneal cavity of mice, as an in vivo source of alternatively activated macrophages. At 3 wk postinfection, the peritoneal exudate cell population is dominated by macrophages, termed nematode-elicited macrophages (NeMphi), that display IL-4-dependent features such as the expression of arginase 1, RELM-alpha (resistin-like molecule alpha), and Ym1. Since increasing evidence suggests that macrophages show functional adaptivity, the response of NeMphi to proinflammatory Th1-activating signals was investigated to determine whether a switch between alternative and classical activation could occur in macrophages differentiated in an in vivo infection setting. Despite the long-term exposure to Th2 cytokines and antiinflammatory signals in vivo, we found that NeMphi were not terminally differentiated but could develop a more classically activated phenotype in response to LPS and IFN-gamma. This was reflected by a switch in the enzymatic pathway for arginine metabolism from arginase to inducible NO synthase and the reduced expression of RELM-alpha and Ym1. Furthermore, this enabled NeMphi to become antimicrobial, as LPS/IFN-gamma-treated NeMphi produced NO that mediated killing of Leishmania mexicana. However, the adaptation to antimicrobial function did not extend to key regulatory pathways, such as IL-12 production, which remained unaltered.
Original languageEnglish
Pages (from-to)3084-3094
Number of pages11
JournalThe Journal of Immunology
Volume182
Issue number5
DOIs
Publication statusPublished - Mar 2009

Keywords / Materials (for Non-textual outputs)

  • Animals
  • Brugia malayi
  • Cells, Cultured
  • Female
  • Filariasis
  • Inflammation Mediators
  • Leishmania major
  • Leishmaniasis, Cutaneous
  • Macrophage Activation
  • Macrophages, Peritoneal
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Signal Transduction
  • Th1 Cells
  • Th2 Cells

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