Netrin-1: A Modulator of Macrophage Driven Acute and Chronic Inflammation

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.

Keywords: acute inflammation; chronic inflammation; netrin-1; neuronal guidance protein.

Figure 1

Netrin-1 in acute inflammation. Acute inflammation is defined by a rapid influx of neutrophils into the inflamed tissue to combat the intruding pathogen. This is followed by a monocyte recruitment to extend the rapid immune response. In many different models, it has been shown that netrin-1 can very effectively mitigate the influx of neutrophils and monocytes and thereby dampen the acute inflammatory response. The acute, initial phase is followed by a resolving phase, in which neutrophils undergo apoptosis and are taken up by monocytes. The efferocytosis in turn promotes the differentiation of pro-inflammatory into anti-inflammatory monocytes. This phenotype switch and the monocyte egress in acute inflammation is facilitated by netrin-1.

Figure 2

Netrin-1 in atherosclerosis. Subendothelial lipoprotein accumulation incite a proinflammatory activation of the endothelial cells and promote monocyte influx into the developing atherosclerotic plaque. As lipoproteins undergo various modifications, such as oxidation and hydrolysis, they are taken up by monocytes and form proinflammatory foam cells. In this inflammatory milieu chronically, activated macrophages secrete netrin-1, which recruit further monocytes and retain macrophages in the tissue until they undergo apoptosis and form the detrimental necrotic core. Netrin-1 further mitigates pro-resolving macrophage differentiation and efferocytosis. Moreover, netrin-1-secreting macrophages advance the plaque further by recruiting smooth muscle cells into the developing plaque, which can themselves become macrophages and promote the ongoing progression of the plaque.