Functional Characterization of Lymphotoxin-beta-Rezeptor Activation in Inflammation
Final Report Abstract
Our previous studies indicated that LTβR activation by T cell derived LTα1β2 controls and down-regulates intestinal inflammation. Our new results demonstrate that LTβR activation on primary mouse macrophages results in induction of tripartite motif containing (TRIM)30α, which negatively regulates NF-kB activation induced by TLR signaling. LTβR activation results in a down-regulation of pro-inflammatory cytokine and mediator expression upon TLR re-stimulation, demonstrating that LTβR signaling is involved in the induction of TLR crosstolerance. Concordantly, LTβR activation on bone marrow-derived macrophages induced cross-tolerance to TLR4 and TLR9 ligands in vitro. Furthermore, we have generated cell type-specific LTβR-deficient mice with ablation of LTβR expression on macrophages/neutrophils (LTβRflox/floxxLysM-Cre). In bone marrow-derived macrophages derived from these mice LTβR-induced cross-tolerance to TLR4 and TLR9 ligands was impaired and these mice are resistant to LTβR-induced TLR4 tolerance in vivo. Collectively, our data indicate that LTβR activation on macrophages by T cell-derived lymphotoxin α1β2 controls pro-inflammatory responses by activation of a TRIM30α controlled, counterregulatory signaling pathway to protect against exacerbating inflammatory reactions. Furthermore, our previous studies indicated that LTβR activation is crucial for the downregulation of intestinal inflammation. Mice with a conditional ablation of LTβR expression on macrophages/neutrophils 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 proinflammatory cytokines in our experimental model. Signaling pathway analysis clearly demonstrated that LTβR-induced TRIM30α expression is mediated by an IκBα-dependent signaling pathway. Furthermore, the LTβR-induced TRIM30α expression seems to be TRAF3 dependent. Taken together, our data demonstrate that LTβR activation on macrophages by CD4+ T cell derived LTα1β2 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.
Publications
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Rel A and Rel B in distinct thymocyte populations control lymphotoxin signalingdependent IL-17 production in γδ T cells. 2011, Immunity 34: 364
Powolny-Budnicka, I., Riemann, M., Tänzer, S., Schmid, RM., Hehlgans, T., and Weih, F.
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Lymphotoxin-beta receptor activation on macrophages amerliorates acute DSS-induced intestinal inflammation in a TRIM30α-dependent manner. 2012a, Mol. Immunol., 2:128
Wimmer, N., Huber, B., Wege, AK., Barabas, N., Pfeffer, K., and Hehlgans, T.
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Lymphotoxin-beta receptor activation on macrophages induces cross-tolerance to TLR4 and TLR9 ligands. 2012, J. Immunol. 188:3426
Wimmer, N., Huber, B., Barabas, N., Röhrl, J., Pfeffer, K., and Hehlgans, T.
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Endothelial cell-specific Lymphotoxin-beta receptor signalling is critical for ymph node development and HEV formation. 2013, J. Exp. Med., 11: 210
Onder, L., Danuser, R., Scandella, E., Firner, S., Chai, Q., Hehlgans, T., Stein, J., Ludewig, B.
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Lymphotoxin-beta receptor signalling regulates cytokine expression via TRIM30α in a TRAF3-dependent manner. 2013. Mol. Immunol, 54: 40
Wimmer, N., Heigl, U., Klingseisen, L., Schneider-Brachert, W., Hehlgans, T.
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Maturation of lymph node fibroblastic reticular cells from myofibroblastic precursors is critical for antiviral immunity. 2013, Immunity, 38: 1013
Chai, Q., Onder, L., Scandella, E., Gil-Cruz,C., Perez-Shibayama, C., Cupovic, J., Danuser, R., Sparwasser, T., Luther, SA., Thiel, V., Rülicke, T., Stein, JV., Hehlgans, T., Ludewig, B.
