Abstract
Netrins belong to the family of laminin-like secreted proteins, which guide axonal migration and neuronal growth in the developing central nervous system. Over the last 20 years, it has been established that netrin-1 acts as a chemoattractive or chemorepulsive cue in diverse biological processes far beyond neuronal development. Netrin-1 has been shown to play a central role in cell adhesion, cell migration, proliferation, and cell survival in neuronal and non-neuronal tissue. In this context, netrin-1 was found to orchestrate organogenesis, angiogenesis, tumorigenesis, and inflammation. In inflammation, as in neuronal development, netrin-1 plays a dichotomous role directing the migration of leukocytes, especially monocytes in the inflamed tissue. Monocyte-derived macrophages have long been known for a similar dual role in inflammation. In response to pathogen-induced acute injury, monocytes are rapidly recruited to damaged tissue as the first line of immune defense to phagocyte pathogens, present antigens to initiate the adaptive immune response, and promote wound healing in the resolution phase. On the other hand, dysregulated macrophages with impaired phagocytosis and egress capacity accumulate in chronic inflammation sites and foster the maintenance—and even the progression—of chronic inflammation. In this review article, we will highlight the dichotomous roles of netrin-1 and its impact on acute and chronic inflammation.
Highlights
Jin et al [80] demonstrated the importance of netrin-1 in tumor development under hypoxia, which is a microenvironment condition of non-small cell lung cancer by the detection of an epithelial-to-mesenchymal transition, which is mediated by netrin-1 through the phosphoinositide 3 kinase/AKT pathway
Even though much has been learned over the last two decades since netrin-1 was first described outside the central nervous system, many new questions have emerged
Most studies show that the regulation of netrin-1 is critically involved in acute (Figure 1) and chronic inflammation (Figure 2)
Summary
The name netrin originates from the Sanskrit word netr, which means “the one who guides.” This reflects the fact that these laminin-like secreted neuronal guidance proteins were initially described as guidance cues in the developing central nervous system, where they act either as chemoattractive or as chemorepulsive cues. The importance of netrin-1 was shown in human tumors, such as brain tumors, neuroblastomas, prostate cancer, pancreatic cancer, and colorectal cancer In these tumors, the gain of netrin-1 or the deletion of Unc5b and DCC prevents tumor cells from undergoing apoptosis and thereby promotes tumor growth and metastases [12]. Over the 30 years since its discovery, it has been well established that netrin-1 is involved in diverse biological processes far beyond the neuronal axon guidance In this context, netrin-1 was found to play an important role in organogenesis [22], angiogenesis [23], tumorigenesis [11,24], promoting epithelium repair after injury [25], and inflammation. Given the numerous receptors and dichotomous signaling of netrin, it is not surprising that netrin-1 plays divergent roles in various settings of acute and chronic inflammation
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