Contribution of Ninjurin1 to Toll-Like Receptor 4 Signaling and Systemic Inflammation

Abstract

Nerve injury-induced protein (Ninjurin [Ninj]) 1 is an adhesion molecule originally identified in Schwann cells after nerve injury, whereas it is also expressed in leukocytes, epithelium, endothelium, and various organs, and is induced under inflammatory conditions. Its contribution to inflammation was so far restricted to the nervous system and exclusively attributed to its role during leukocyte migration. We hypothesized a proinflammatory role for Ninj1 also outside the nervous system. To elucidate its impact during inflammation, we analyzed expression levels and its contribution to inflammation in septic mice and studied its effect on inflammatory signaling in vitro. The effect on inflammation was analyzed by genetic (only in vitro) and pharmacologic repression in septic mice (cecal ligation and puncture) and cell culture, respectively. Repression of Ninj1 by an inhibitory peptide or small interfering RNA attenuated LPS-triggered inflammation in macrophages and endothelial cells by modulating p38 phosphorylation and activator protein-1 activation. Inhibition of Ninj1 in septic mice reduced systemic and pulmonary inflammation as well as organ damage, and ameliorated survival after 24 hours. Ninj1 is elevated under inflammatory conditions and contributes to inflammation not only by mediating leukocyte migration, but also by modulating Toll-like receptor 4-dependent expression of inflammatory mediators. We assume that, owing to both mechanisms, inhibition reduces systemic inflammation and organ damage in septic mice. Our data contribute to a better understanding of the complex inflammatory mechanisms and add a novel therapeutic target for inflammatory conditions such as sepsis.

NINJ2– A novel regulator of endothelial inflammation and activation

“…Endothelial cell activation and inflammation is the initial and critical step in the process of atherosclerosis [27,28], and our results showed that overexpression of NINJ2 can exacerbate the systemic activation and inflammation of the endothelial. Two recent studies have reported that NINJ1 can regulate the LPS-induced inflammatory response in macrophages and endothelial [25,29], which is consistent with our current findings and supports our data for further step.…”

“…5B). To further prove that the transcription factor c-jun can directly binding to the first intron of NINJ2, an EMSA was performed using a double-stranded oligonucleotide encompassing the region from Previous studies have shown that NINJ1 can modulate the activation of the activator protein-1 (AP-1), which is comprised of a c-jun homodimer or a c-jun/fos heterodimer [25]. Here we investigated whether NINJ2 can regulate c-jun in a similar way.…”

Key Vitamin D Target Genes with Functions in the Immune System

“…CD93 may have a protective role in autoimmune encephalomyelitis via the control of the severity of inflammation, apoptosis and bystander neuronal injury [68]. NINJ1 is a transmembrane protein expressed primarily in myeloid and endothelial cells [69] but it was first described in the peripheral nervous system inducing neurite extension. In the latter context, NINJ1 was found to be involved in the immune pathogenesis of multiple sclerosis [70].…”

Detrimental Role of Nerve Injury-Induced Protein 1 in Myeloid Cells under Intestinal Inflammatory Conditions

“…Recent studies reveal that besides the nervous system, Ninj1 regulates several inflammatory diseases. Ninj1 inhibition reduces susceptibility to systemic inflammation, liver damage, and pulmonary inflammation in septic mice [4]. In addition, we have previously reported that Ninj1-deficient mice display a mild lung pulmonary fibrosis phenotype associated with the interaction between macrophages and alveolar epithelial cells [5].…”

“…After triggering of this complex cascade, macrophages produce pro-inflammatory cytokines and chemokines to amplify the inflammatory signal and recruit leukocytes to the lesion site. Ninj1 is reported to modulate the TLR4 signaling cascade, resulting in increased pathogenesis in septic mice [4]. Abundant studies have demonstrated that lipopolysaccharides (LPS) activate TLR families and PKC isoforms [21][22][23][24][25].…”