The Proteoglycan Biglycan Enhances Antigen-Specific T Cell Activation Potentially via MyD88 and TRIF Pathways and Triggers Autoimmune Perimyocarditis

Abstract

Biglycan is a proteoglycan ubiquitously present in extracellular matrix of a variety of organs including heart and has been reported to be overexpressed in myocardial infarction. Myocardial infarction may be complicated by perimyocarditis through to date unclear mechanisms. Our aim was to investigate the capacity of TLR2/TLR4 ligand biglycan to enhance the presentation of specific Ags released upon cardiomyocyte necrosis. In vitro, Ova-pulsed bone-marrow derived dendritic cells from WT (C57BL/6), TLR2-, TLR4-, MyD88- or TRIF- deficient mice were co-treated with LPS, biglycan or vehicle and incubated with Ova-recognizing MHCI- or MHCII-restricted T cells. Biglycan enhanced Ova-specific cross-priming by more than 80% to MHCI-restricted T cells in both TLR2 - and TLR4 – pathway dependent manner. Accordingly, biglycan-induced cross-priming by both MyD88- and TRIF-deficient DCs was strongly diminished. Ova-specific activation of MHCII-restricted T cells was predominantly TLR4-dependent. Our first in vivo correlate was a model of experimental autoimmune perimyocarditis triggered by injection of cardiac-Ag pulsed DCs (BALB/c). Biglycan-treated DCs triggered perimyocarditis in extent and intensity comparable to LPS-treated DCs (average scores 1.3±0.3 and 1.5±0.4, respectively). Substitution with TLR4-deficient DCs abolished this effect. In a second in vivo approach, WT and biglycan-deficient mice were followed two weeks after induction of myocardial infarction. WT mice demonstrated significantly higher myocardial T-lymphocyte infiltration in comparison to biglycan-deficient animals. We conclude that TLR2/4 ligand biglycan, a component of the myocardial matrix, may enhance Ag-specific T cell priming via MyD88 and TRIF and stimulate autoimmune perimyocarditis.

Small leucine-rich proteoglycans orchestrate receptor crosstalk during inflammation

“…MHC II-dependent, antigen-specific T-cell activation is mainly mediated by TLR4. 63 These results were further confirmed in experimental autoimmune perimyocarditis (EAP). In this model, biglycan signals via TLR4 as a potent amplifier of specific cardiomyocyte antigen presentation to prime T cells.…”

“…8,63 In lupus nephritis (LN), a renal manifestation of systemic lupus erythematosus, biglycan, induces macrophages and dendritic cells to express chemokine (C-X-C) ligand 13 (CXCL13), the major chemoattractant for B and B1 cells. This is brought about by biglycan signaling through TLR2/4 and initiating the production of ROS.…”

“…Biglycan initiates an autoreactive immune response without influencing postinfarction fibrosis or infiltration of antigen presenting cells. 63 TLR and NOD-like receptors, as both ligands and receptors contain LRRs in their protein structure. In this context, the scarcity of data addressing the role of SLRPs in the regulation of inflammation is surprising.…”

Axonally derived matrilin-2 induces proinflammatory responses that exacerbate autoimmune neuroinflammation

“…While signal transduction through most TLRs is solely dependent on MyD88, TLR4 can also signal through an alternative TRIF-dependent mechanism. MyD88-mediated activation of downstream pathways involves phosphorylation of the MAP kinases ERK and p38 as well as the transcription factor NF-κB (13,32,36). Although most TLR-activating ECM molecules signal through the same TLRs, they all have obvious structural differences and trigger differential responses and biological outcomes.…”

“…In principle, blockade of MATN2 signaling or its neutralization could be a novel therapeutic strategy for early relapsing-remitting MS, in which severe lesional axonal injury is often a feature. so-called DAMPs (9,13,14,30,32), which are released from cells following tissue stress or injury. DAMPs are recognized by innate immunity receptors and, functioning in a similar way to pathogen-associated molecular patterns (33), they induce or increase an acute local proinflammatory response.…”