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Lymphotoxin-beta receptor activation on macrophages ameliorates acute DSS-induced intestinal inflammation in a TRIM30α-dependent manner.

Abstract
Our previous studies indicated that LTβR activation mainly by T cell derived LTα₁β₂ is crucial for the control and down-regulation of intestinal inflammation. In order to dissect the cellular and molecular role of LTβR activation in the experimental model of DSS-induced intestinal inflammation, we have generated cell type-specific LTβR-deficient mice with specific ablation of LTβR expression on macrophages/neutrophils (LTβR((flox/flox))×LysM-Cre). These mice develop an exacerbated intestinal inflammation in our experimental model indicating that LTβR expression on macrophages/neutrophils is responsible for the control and down-regulation of the inflammatory reaction. These results were verified by adoptive transfer experiments of BMDM from wild-type and LTβR-deficient mice. Furthermore, transfer of activated CD4+ T cells derived from wild-type mice, but not from LTβR ligand-deficient mice attenuated the signs of intestinal inflammation. Finally, we demonstrate that LTβR activation on BMDM results in induction of TRIM30α, a negative regulator of NFκB activation. Concordantly, ablation of LTβR signaling results in the inability to induce TRIM30α expression concomitant with an increased expression of pro-inflammatory cytokines in our experimental model. Taken together, our data demonstrate that LTβR activation on macrophages by CD4+ T cell derived LTαβ controls the pro-inflammatory response by activation of a TRIM30α-dependent signaling pathway, crucial for the down-regulation of the inflammatory response in this experimental model.
AuthorsNadin Wimmer, Barbara Huber, Anja K Wege, Nicola Barabas, Johann Röhrl, Klaus Pfeffer, Thomas Hehlgans
JournalMolecular immunology (Mol Immunol) Vol. 51 Issue 2 Pg. 128-35 (Jun 2012) ISSN: 1872-9142 [Electronic] England
PMID22437076 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2012 Elsevier Ltd. All rights reserved.
Chemical References
  • Intracellular Signaling Peptides and Proteins
  • Lymphotoxin beta Receptor
  • TRIM30 alpha protein, mouse
  • Dextran Sulfate
Topics
  • Animals
  • CD4-Positive T-Lymphocytes (immunology, metabolism)
  • Coculture Techniques
  • Colitis (chemically induced, immunology, metabolism)
  • Dextran Sulfate (toxicity)
  • Disease Models, Animal
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Intracellular Signaling Peptides and Proteins (immunology, metabolism)
  • Lymphotoxin beta Receptor (immunology, metabolism)
  • Macrophages (immunology, metabolism)
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction

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