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.

Overproduction of Tenascin‐C Driven by Lipid Accumulation in the Liver Aggravates Hepatic Ischemia/Reperfusion Injury in Steatotic Mice

“…Hence, our results suggest that inhibition of Tnc is a promising therapeutic strategy to curb excessive inflammation in suboptimal steatotic livers and to maximize their successful use in organ transplantation. In addition to hepatic IRI, Tnc has been considered a viable therapeutic candidate for targeting in several other inflammatory pathologies . However, this field is still in its infancy, and more studies aimed at better understanding the biological complexity of Tnc, combined with technological advancements, are needed to generate improved therapeutic modalities to inhibit Tnc in both experimental and clinical settings …”

“…Notably, Tnc is rapidly induced in adult tissues in response to pathological stress . Although Tnc is necessary for physiological tissue repair, its misregulated expression has been associated with a variety of pathological conditions, which include rheumatoid arthritis, cancer, myocardial infarction, hepatitis, and hepatic IRI . Tnc is a pleiotropic molecule implicated in various cellular functions, with regulation of cell adhesion and migration being among the most characterized .…”

“…A number of studies have reported that Tnc affects leukocyte recruitment, T cell activation and proliferation, and the production of several inflammatory cytokines . Tnc is an immunomodulatory protein with complex tissue‐specific interactions and functions, which are dependent on the type of tissue injury . Normal and steatotic livers undergo different mechanisms of ischemic injury .…”

“…(16) Although Tnc is necessary for physiological tissue repair, its misregulated expression has been associated with a variety of pathological conditions, which include rheumatoid arthritis, cancer, myocardial infarction, hepatitis, and hepatic IRI. (17)(18)(19)(20)(21)(22) Tnc is a pleiotropic molecule implicated in various cellular functions, with regulation of cell adhesion and migration being among the most characterized. (18) Growing evidence now points to Tnc as a key regulator of both innate and adaptive immunity.…”

“…(17,18,(23)(24)(25)(26) Tnc is an immunomodulatory protein with complex tissue-specific interactions and functions, which are dependent on the type of tissue injury. (22,24) Normal and steatotic livers undergo different mechanisms of ischemic injury. (4) The present study assesses the effect of hepatic lipid accumulation on Tnc expression, and it tests whether Tnc deletion ameliorates the outcome of steatotic liver IRI.…”