Heterogeneity of macrophage activation in anti-Thy-1.1 nephritis

A. Minto, Lars Peter Erwig, Andrew Jackson Rees

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Macrophages infiltrating glomeruli in telescoped nephrotoxic nephritis are programmed. The purpose of this study was to assess whether macrophages infiltrating glomeruli of rats with passively induced injury become similarly programmed, and to determine whether macrophage commitment is an early event. Glomerular macrophages isolated from rats with resolving and proliferative anti-Thy-1 nephritis were examined for nitric oxide (NO) generation and expression of lysosomal hydrolases. After a single injection of Thy-1 antibody the cells generated large amounts of NO that was attenuated ex vivo by transforming growth factor-beta and other anti-inflammatory cytokines. In contrast macrophages infiltrating glomeruli immediately after a second injection of Thy-1 antibody generated No spontaneously and were unresponsive to alternative activation. beta-Glucuronidase expression was used as a second independent assay for macrophage activation and the results confirmed the observations made for NO. Furthermore, macrophages infiltrating the glomerulus after the second antibody injection exhibited a striking dichotomy in that 70% of the cells behave as programmed by interferon-gamma and 30% by transforming growth factor-beta. The results show that macrophage commitment occurs very early after monocyte migration and that infiltration itself does not invariably induce macrophage programming. it demonstrates that macrophages infiltrating inflamed glomeruli at the same time do not respond uniformly, but are capable of engaging different activation programs. This emphasizes the critical importance of the underlying disease process for macrophage functional development in an inflamed environment.

Original languageEnglish
Pages (from-to)2033-2041
Number of pages8
JournalAmerican Journal of Pathology
Volume163
Issue number5
Publication statusPublished - Nov 2003

Keywords

  • EXPERIMENTAL GLOMERULONEPHRITIS
  • ALTERNATIVE ACTIVATION
  • NEPHROTOXIC NEPHRITIS
  • GLOMERULAR INJURY
  • INTERFERON-GAMMA
  • EXPRESSION
  • CELLS
  • RESPONSES
  • RECEPTORS
  • MODEL

Cite this

Minto, A., Erwig, L. P., & Rees, A. J. (2003). Heterogeneity of macrophage activation in anti-Thy-1.1 nephritis. American Journal of Pathology, 163(5), 2033-2041.

Heterogeneity of macrophage activation in anti-Thy-1.1 nephritis. / Minto, A.; Erwig, Lars Peter; Rees, Andrew Jackson.

In: American Journal of Pathology, Vol. 163, No. 5, 11.2003, p. 2033-2041.

Research output: Contribution to journalArticle

Minto, A, Erwig, LP & Rees, AJ 2003, 'Heterogeneity of macrophage activation in anti-Thy-1.1 nephritis', American Journal of Pathology, vol. 163, no. 5, pp. 2033-2041.
Minto, A. ; Erwig, Lars Peter ; Rees, Andrew Jackson. / Heterogeneity of macrophage activation in anti-Thy-1.1 nephritis. In: American Journal of Pathology. 2003 ; Vol. 163, No. 5. pp. 2033-2041.
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AB - Macrophages infiltrating glomeruli in telescoped nephrotoxic nephritis are programmed. The purpose of this study was to assess whether macrophages infiltrating glomeruli of rats with passively induced injury become similarly programmed, and to determine whether macrophage commitment is an early event. Glomerular macrophages isolated from rats with resolving and proliferative anti-Thy-1 nephritis were examined for nitric oxide (NO) generation and expression of lysosomal hydrolases. After a single injection of Thy-1 antibody the cells generated large amounts of NO that was attenuated ex vivo by transforming growth factor-beta and other anti-inflammatory cytokines. In contrast macrophages infiltrating glomeruli immediately after a second injection of Thy-1 antibody generated No spontaneously and were unresponsive to alternative activation. beta-Glucuronidase expression was used as a second independent assay for macrophage activation and the results confirmed the observations made for NO. Furthermore, macrophages infiltrating the glomerulus after the second antibody injection exhibited a striking dichotomy in that 70% of the cells behave as programmed by interferon-gamma and 30% by transforming growth factor-beta. The results show that macrophage commitment occurs very early after monocyte migration and that infiltration itself does not invariably induce macrophage programming. it demonstrates that macrophages infiltrating inflamed glomeruli at the same time do not respond uniformly, but are capable of engaging different activation programs. This emphasizes the critical importance of the underlying disease process for macrophage functional development in an inflamed environment.

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