Mapping tenascin-C interaction with toll-like receptor 4 reveals a new subset of endogenous inflammatory triggers

Zuliani-Alvarez, Lorena; Marzeda, Anna M.; Deligne, Claire; Schwenzer, Anja; McCann, Fiona E.; Marsden, Brian D.; Piccinini, Anna M.; Midwood, Kim S.

doi:10.1038/s41467-017-01718-7

Cited by 86 publications

(85 citation statements)

References 62 publications

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“…This occurs via the binding of damage associated molecular patterns (DAMPs) including HMGB1, heat shock and S100 proteins 100,101 . Tenascin-C a matrix protein induced upon tissue damage also activates TLR4 mediated sterile inflammation 102 . Binding of these ligands to TLR4 induces a high alert state, favouring the development of chronic inflammation 50,103 .…”

Section: Cross Talk Between Cells Of Mesenchymal Originmentioning

confidence: 99%

Pathogenic stromal cells as therapeutic targets in joint inflammation

et al. 2018

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Section: Cross Talk Between Cells Of Mesenchymal Originmentioning

confidence: 99%

Pathogenic stromal cells as therapeutic targets in joint inflammation

et al. 2018

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“…Crystallisation of the FBG domain of human tenascin-C in complex with Fab fragments of C3 revealed interactions in the X-ray structure are mediated by hydrogen bonds and three layer pi:pi stacking, predominantly between one of the two Fab chains (figure 2A,B). Comparison of the TLR4 binding epitope10 with the Fab epitope in FBG predict that antibody binding will abrogate tenascin-C’s ability to activate TLR4 by preventing access of the receptor to residues (S2131 and I2133) in FBG that are required for optimal binding to TLR4. This was validated experimentally by demonstration that preincubation of FBG with C3 inhibits binding of FBG to purified recombinant TLR4 in a solid phase binding assay (IC 50 45.56 nM)(figure 2C) and that preincubation of FBG with C3 blocks the ability of FBG to induce cytokine synthesis in primary human macrophages, while C3 had no effect on LPS-induced cytokine release (figure 2D).…”

Section: Resultsmentioning

confidence: 99%

“…Mapping the active domain within tenascin-C revealed a unique structural epitope in the fibrinogen-like globe (FBG) that is essential for binding to and activating TLR4 8 10. Distinct modes of receptor activation and diverse downstream signalling induced by FBG compared with pathogenic TLR4 agonists,11 revealed an opportunity to ablate pathological ‘sterile’ inflammation, leaving intact host defence against infection.…”

Section: Introductionmentioning

confidence: 99%

Targeting early changes in the synovial microenvironment: a new class of immunomodulatory therapy?

et al. 2018

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ObjectivesControlled immune responses rely on integrated crosstalk between cells and their microenvironment. We investigated whether targeting proinflammatory signals from the extracellular matrix that persist during pathological inflammation provides a viable strategy to treat rheumatoid arthritis (RA).MethodsMonoclonal antibodies recognising the fibrinogen-like globe (FBG) of tenascin-C were generated by phage display. Clones that neutralised FBG activation of toll-like receptor 4 (TLR4), without impacting pathogenic TLR4 activation, were epitope mapped by crystallography. Antibodies stained synovial biopsies of patients at different stages of RA development. Antibody efficacy in preventing RA synovial cell cytokine release, and in modulating collagen-induced arthritis in rats, was assessed.ResultsTenascin-C is expressed early in the development of RA, even before disease diagnosis, with higher levels in the joints of people with synovitis who eventually developed RA than in people whose synovitis spontaneously resolved. Anti-FBG antibodies inhibited cytokine release by RA synovial cells and prevented disease progression and tissue destruction during collagen-induced arthritis.ConclusionsEarly changes in the synovial microenvironment contribute to RA progression; blocking proinflammatory signals from the matrix can ameliorate experimental arthritis. These data highlight a new drug class that could offer early, disease-specific immune modulation in RA, without engendering global immune suppression.

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“…Tenascins belong to the fibrinogen-related proteins (FREPs) family that all bear an FBG domain. If not all FBG domains are able to activate TLR4, Zuliani-Alvarez et al showed that the presence of a cationic ridge in the FBG domain defined the capacity to activate TLR4 46 .…”

Section: Discussionmentioning

confidence: 99%

Tenascin-C inactivation impacts lung structure and function beyond lung development

Gremlich

Roth‐Kleiner

Equey

et al. 2020

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Johannes c. Schittny 4 & tiziana p. cremona 4 tenascin-c (tnc) is an extracellular matrix protein expressed at high levels during lung organogenesis. Later, tnc is only transiently de novo expressed to orchestrate tissue repair in pathological situations. We previously showed that TNC inactivation affects lung development and thus evaluated here the implications on lung function in newborn/adult mice. Respiratory function parameters were measured in anesthetized and mechanically ventilated wild-type (WT) and TNC-deficient mice at 5 (P5) and 90 (P90) days of age under basal conditions, as well as following high tidal volume (HTV) ventilation. At P5, TNC-deficient mice showed an increased static compliance (Cst) and inspiratory capacity (IC) relative to WT at baseline and throughout HTV. At P90, however, Cst and IC were only elevated at baseline. Control non-ventilated newborn and adult TNC-deficient mice showed similar lung morphology, but less alpha smooth muscle actin (α-SMA) around small airways. SMA + cells were decreased by 50% in adult TNCdeficient lungs and collagen layer thickened around small airways. Increased surfactant protein C (SPc) and altered tGfβ and TLR4 signaling pathways were also detected. Thus, TNC inactivation-related defects during organogenesis led to persisting functional impairment in adulthood. this might be of interest in the context of pulmonary diseases with thickened airway smooth muscle layer or ventilation heterogeneity, like asthma and COPD.

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Mapping tenascin-C interaction with toll-like receptor 4 reveals a new subset of endogenous inflammatory triggers

Cited by 86 publications

References 62 publications

Pathogenic stromal cells as therapeutic targets in joint inflammation

Pathogenic stromal cells as therapeutic targets in joint inflammation

Targeting early changes in the synovial microenvironment: a new class of immunomodulatory therapy?

Tenascin-C inactivation impacts lung structure and function beyond lung development

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