Endogenous Control of Immunity against Infection: Tenascin-C Regulates TLR4-Mediated Inflammation via MicroRNA-155

Endogenous molecules generated upon pathogen invasion or tissue damage serve as danger signals that activate host defense; however, their precise immunological role remains unclear. Tenascin-C is an extracellular matrix glycoprotein that is specifically induced upon injury and infection. Here, we show that its expression is required to generate an effective immune response to bacterial lipopolysaccharide (LPS) during experimental sepsis in vivo. Tenascin-C enables macrophage translation of proinflammatory cytokines upon LPS activation of toll-like receptor 4 (TLR4) and suppresses the synthesis of anti-inflammatory cytokines. It mediates posttranscriptional control of a specific subset of inflammatory mediators via induction of the microRNA miR-155. Thus, tenascin-C plays a key role in regulating the inflammatory axis during pathogenic activation of TLR signaling. [Display omitted] ► Endogenous danger signals mediate effective immunity against pathogenic infection ► Tenascin-C is required to generate a proinflammatory response to LPS in vivo ► Tenascin-C post-transcriptionally regulates TNF-α production by macrophages ► Tenascin-C controls TNF-α translation by driving microRNA-155 expression Endogenous molecules generated upon infection help to provoke an immune response to pathogenic invasion. However, it is not clear how these danger signals activate signaling cascades that culminate in the expression of proinflammatory genes designed to combat infection. Piccinini and Midwood now show a unique requirement of the extracellular matrix protein tenascin-C in macrophages at the forefront of bacterial invasion, where it is needed to drive production of microRNA miR-155, which enables sustained expression of proinflammatory cytokines such as TNF-α.