Internal Affairs: Tenascin-C as a Clinically Relevant, Endogenous Driver of Innate Immunity

Abstract

To protect against danger, the innate immune system must promptly and accurately sense alarm signals, and mount an appropriate response to restore homeostasis. One endogenous trigger of immunity is tenascin-C, a large hexameric protein of the extracellular matrix. Upregulated upon tissue injury and cellular stress, tenascin-C is expressed during inflammation and tissue remodeling, where it influences cellular behavior by interacting with a multitude of molecular targets, including other matrix components, cell surface proteins, and growth factors. Here, we discuss how these interactions confer upon tenascin-C distinct immunomodulatory capabilities that make this matrix molecule necessary for efficient tissue repair. We also highlight in vivo studies that provide insight into the consequences of misregulated tenascin-C expression on inflammation and fibrosis during a wide range of inflammatory diseases. Finally, we examine how its unique expression pattern and inflammatory actions make tenascin-C a viable target for clinical exploitation in both diagnostic and therapeutic arenas.

Keywords: extracellular matrix; fibroblast; fibrosis; inflammation; inflammatory disease; innate immunity; integrin; macrophage; toll-like receptor 4.

Figure 1.

Tenascin-C modulates physiological and pathological inflammation. (A) Tenascin-C, upregulated upon cellular stress or tissue injury, is capable of binding to TLR4 and integrins α9β1 and αVβ3 on the cell surface and inducing NFκB-mediated gene expression. In macrophages and DCs, tenascin-C stimulates the secretion of a wide array of proinflammatory cytokines and chemokines, provoking an inflammatory response. Among these soluble mediators, IL-1β, IL-6, and IL-23 promote the differentiation of Th17 cells. Tenascin-C also polarizes myeloid cell phenotypes in a context-specific manner, for example, generating reparative macrophages or facilitating lipid uptake, promoting macrophages to form foam cells. In fibroblasts, tenascin-C stimulates expression of a different subset of mediators; this includes the cytokine IL-6 but also molecules such as αSMA, TGF-β and high levels of collagen that promote tissue remodeling. Tenascin-C is also capable of inhibiting naive T-cell activation. Typically, tenascin-C expression is downregulated, allowing for the resolution of inflammation and completion of tissue repair. However, a number of questions regarding the mode of action of tenascin-C still need answering: (1) What are the exact mechanisms leading to tenascin-C upregulation? (2) Does the form of tenascin-C (hexabrachion/monomer/domains cleaved by proteolytic enzymes) influence receptor binding and activation? (3) How exactly, and why, is tenascin-C expression downregulated and protein cleared from the tissue? Answering each of these questions will be crucial to understanding how and why persistent expression of tenascin-C leads to a chronic inflammation that can trigger the development of a number of inflammatory diseases, summarized in (B). Abbreviations: TLR4, toll-like receptor 4; NFκB, nuclear factor kappa-light-chain-enhancer of activated B cells; DC, dendritic cell; IL = interleukin; αSMA, alpha-smooth muscle actin; TGF-β, transforming growth factor beta; TNF, tumor necrosis factor; MMP, matrix metalloproteinase; CCL, C-C motif chemokine ligand; CXCL, chemokine receptor; oxLDL, oxidized low-density lipoprotein.