title: 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.
authors.affiliation: Institute of Immunology, University of Regensburg, 93053 Regensburg, Germany.
authors.forename: Nadin
authors.initials: N
authors.lastname: Wimmer
authors.forename: Barbara
authors.initials: B
authors.lastname: Huber
authors.forename: Anja K
authors.initials: AK
authors.lastname: Wege
authors.forename: Nicola
authors.initials: N
authors.lastname: Barabas
authors.forename: Johann
authors.initials: J
authors.lastname: Röhrl
authors.forename: Klaus
authors.initials: K
authors.lastname: Pfeffer
authors.forename: Thomas
authors.initials: T
authors.lastname: Hehlgans
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018920:Coculture Techniques; D003092:Colitis / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism*; D016264:Dextran Sulfate / Q000633:toxicity; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D047908:Intracellular Signaling Peptides and Proteins / Q000276:immunology / Q000378:metabolism*; D053259:Lymphotoxin beta Receptor / Q000276:immunology / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D053259:Lymphotoxin beta Receptor; C528084:TRIM30 alpha protein, mouse; D016264:Dextran Sulfate