Distinct contributions of TNF receptor 1 and 2 to TNF-induced glomerular inflammation in mice.

Abstract

TNF is an important mediator of glomerulonephritis. The two TNF-receptors TNFR1 and TNFR2 contribute differently to glomerular inflammation in vivo, but specific mechanisms of TNFR-mediated inflammatory responses in glomeruli are unknown. We investigated their expression and function in murine kidneys, isolated glomeruli ex vivo, and glomerular cells in vitro. In normal kidney TNFR1 and TNFR2 were preferentially expressed in glomeruli. Expression of both TNFRs and TNF-induced upregulation of TNFR2 mRNA was confirmed in murine glomerular endothelial and mesangial cell lines. In vivo, TNF exposure rapidly induced glomerular accumulation of leukocytes. To examine TNFR-specific inflammatory responses in intrinsic glomerular cells but not infiltrating leukocytes we performed microarray gene expression profiling on intact glomeruli isolated from wildtype and Tnfr-deficient mice following exposure to soluble TNF ex vivo. Most TNF-induced effects were exclusively mediated by TNFR1, including induced glomerular expression of adhesion molecules, chemokines, complement factors and pro-apoptotic molecules. However, TNFR2 contributed to TNFR1-dependent mRNA expression of inflammatory mediators in glomeruli when exposed to low TNF concentrations. Chemokine secretion was absent in TNF-stimulated Tnfr1-deficient glomeruli, but also significantly decreased in glomeruli lacking TNFR2. In vivo, TNF-induced glomerular leukocyte infiltration was abrogated in Tnfr1-deficient mice, whereas Tnfr2-deficiency decreased mononuclear phagocytes infiltrates, but not neutrophils. These data demonstrate that activation of intrinsic glomerular cells by soluble TNF requires TNFR1, whereas TNFR2 is not essential, but augments TNFR1-dependent effects. Previously described TNFR2-dependent glomerular inflammation may therefore require TNFR2 activation by membrane-bound, but not soluble TNF.

• Authors: Anela Taubitz, Martin Schwarz, Nuru Eltrich, Maja T Lindenmeyer, Volker Vielhauer
• Journal: PloS one (PLoS One) Vol. 8 Issue 7 Pg. e68167 ( 2013) ISSN: 1932-6203 [Electronic] United States
• PMID: 23869211 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Receptors, Tumor Necrosis Factor, Type I
• Receptors, Tumor Necrosis Factor, Type II
• Tnfrsf1a protein, mouse
• Transforming Growth Factors

Topics

• Animals
• Cell Line
• Gene Deletion
• Gene Expression Profiling
• Kidney (metabolism, pathology)
• Leukocytes (metabolism, pathology, physiology)
• Male
• Mice
• Mice, Inbred C57BL
• Oligonucleotide Array Sequence Analysis
• Real-Time Polymerase Chain Reaction
• Receptors, Tumor Necrosis Factor, Type I (genetics, metabolism, physiology)
• Receptors, Tumor Necrosis Factor, Type II (genetics, metabolism, physiology)
• Transforming Growth Factors (pharmacology)