Netrin-1 controls inflammation in response to ischemic stroke through altering microglia phenotype

Abstract

IntroductionThe current approaches that are used to treat ischemic stroke suffer from poor targeting, lack of effectiveness, and potential off-target effects, necessitating the development of new therapeutic strategies to enhance neuronal cell survival and regeneration. This study aimed to investigate the role of microglial Netrin-1 in ischemic stroke, a topic that has not been fully understood.MethodsNetrin-1 levels and its primary receptor expressions were investigated in cerebral microglia from acute ischemic stroke patients and age-matched control subjects. A public database (GEO148350), which supplied RNAseq results for rat cerebral microglia in a middle cerebral artery occlusion (MCAO) model, was analyzed to assess the expression of Netrin-1, its major receptors, and genes related to macrophage function. A microglia-specific gene targeting approach and a delivery system allowing for crossing the blood-brain barrier were applied in a mouse model for ischemic stroke to investigate the role of microglial Netrin-1. Netrin-1 receptor signaling in microglia was observed and the effects on microglial phenotype, apoptosis, and migration were analyzed.ResultsAcross human patients, rat and mouse models, activation of Netrin-1 receptor signaling was mainly conducted via its receptor UNC5a in microglia, which resulted in a shift in microglial phenotype towards an anti-inflammatory or M2-like state, leading to a reduction in apoptosis and migration of microglia. Netrin-1-induced phenotypic change in microglia exerted protective effects on neuronal cells in vivo during ischemic stroke.ConclusionOur study highlights the potential of targeting Netrin-1 and its receptors as a promising therapeutic strategy for promoting post-ischemic survival and functional recovery.

Circulating netrin‐1 levels are reduced and related to corneal nerve fiber loss in patients with diabetic neuropathy

“…In a seminal paper published almost 20 years ago, it was shown that the reversal of neuropathy and vasculopathy in a diabetic murine model were both attributed to netrins 20 . Netrin‐1 plays a key role in a variety of physiological processes, including cell injury, proliferation and migration 21 , and is an emerging player in driving inflammation 22 in a variety of tissues, including the liver 23 , visceral tissue 24 and brain 25 . In a recent study, gene expression profiles of the netrin family were significantly lower in the skin and sural nerve of 88 patients with polyneuropathy, including those with DN and especially those with painful neuropathy, and furthermore correlated with intra‐epidermal nerve fiber density 16 .…”

Molecular Mechanisms of Ischemic Stroke: A Review Integrating Clinical Imaging and Therapeutic Perspectives

“…Polarizing microglia towards the M2-like phenotype is crucial to mitigate inflammatory damage after a stroke, as the M2 phenotype promotes tissue repair and regeneration. In contrast, the M1 phenotype releases proinflammatory cytokines that exacerbate tissue injury [109,110].…”