The neuroimmune guidance cue netrin‐1 controls resolution programs and promotes liver regeneration

Abstract

Hepatic ischemia/reperfusion (I/R) is a major adverse reaction to liver transplantation, hemorrhagic shock, or resection. Recently, the anti-inflammatory properties of the axonal guidance cue netrin-1 were reported. Here, we demonstrate that netrin-1 also impacts the resolution of inflammation and promotes hepatic repair and regeneration during liver I/R injury. In initial studies, we investigated the induction of netrin-1 and its receptors in murine liver tissues after I/R injury. Hepatic I/R injury was performed in mice with a partial genetic netrin-1 deficiency (Ntn1 1/2 ) or wild-type C57BL/6 treated with exogenous netrin-1 to examine the endogenous and therapeutically administered impact of netrin-1. These investigations were corroborated by studies determining the characteristics of intravascular leukocyte flow, clearance of apoptotic neutrophils (polymorphonuclear cells [PMNs]), production of specialized proresolving lipid mediators (SPMs), generation of specific growth factors contributing to the resolution of inflammation, and liver repair. Hepatic I/R was associated with a significant reduction of netrin-1 transcript and protein in murine liver tissue. Subsequent studies in netrin-1-deficient mice revealed lower efficacies in reducing PMN infiltration, proinflammatory cytokine levels, and hepatic-specific injury enzymes. Conversely, mice treated with exogenous netrin-1 exhibited increased liver protection and repair, reducing neutrophil influx into the injury site, decreasing proinflammatory mediators, increasing efferocytosis of apoptotic PMNs, and stimulating local endogenous biosynthesis of SPMs and the generation of specific growth factors. Finally, genetic studies implicated the A2B adenosine receptor in netrin-1-mediated protection during hepatic I/R injury. Conclusion: The present study indicates a previously unrecognized role for netrin-1 in liver protection and its contribution to tissue homeostasis and regeneration. (HEPATOLOGY 2016;63:1689-1705 SEE EDITORIAL ON PAGE 1427H epatic ischemia/reperfusion (I/R) injury, characterized by the restoration of blood flow and reoxygenation, is a major adverse consequence of liver transplantation, hemorrhagic shock, or major hepatic surgery.(1,2) This underlying interruption of blood flow leads to severe changes in hemodynamic mechanisms. As a result, mortality in patients affected from I/R injury is high, because this disorder may also induce hypoxic hepatitis. This form of hepatic injury is particularly characterized by centrilobular liver cells necrosis. The prognosis in critically ill patients is reported to be poor and is accompanied Abbreviations: 19,19,19,19,20-epoxydocosapentaenoic acid; Adora2b, A2B adenosine receptor; ALT, alanine aminotransferase; AST, aspartate aminotransferase; DAB, 3,3 0 -diaminobenzidine; DAPI, 4 0 ,6-diamidino-2-phenylindole; DCC, DCC netrin-1 receptor; EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; HB-EGF, heparin-binding epidermal growth factor; HETE, hydroxyeicosatetraenoic acid; HGF, hepatocyte ...

Netrin‐1 alleviates subarachnoid haemorrhage‐induced brain injury via the PPARγ/NF‐KB signalling pathway

“…As a result, patients suffer from disruption of blood‐brain barrier (BBB), brain oedema, worsening of cognitive functions, etc . Our study is preceded by a number of reports on treatment with exogenous NTN‐1, which can efficiently alleviate inflammation in non‐neural diseases . Our data consolidated that the effects of NTN‐1 treatment in SAH‐induced early brain injury are beneficial, evidenced by reduced brain oedema and improved neurological score.…”

Stem Cell Therapeutics of Acute Liver Diseases, Transplantation, and Regeneration

“…Similarly, severe liver damage can be confirmed on the clinical symptoms of hepatic ischemia/reperfusion, hemorrhagic shock, or resection, decreasing pro-inflammatory mediators, increasing efferocytosis of apoptotic PMNs, endogenous biosynthesis of SPMs and the generation of specific growth factors [156]. Chronic liver disease (CLD) can also be confirmed by decreased thrombopoietin production and accelerated platelet destruction caused by hypersplenism [157]. In case of hepatocellular carcinoma REILD FGF-19 and HGF seems to be important therapeutic markers [158,159].…”

Immunomodulatory Functions of Neuronal Guidance Proteins

“…As a result, netrin-1 significantly shortens the time required for resolution, which is a quantitative measure of resolution and tissue regeneration. Extension of this work showed that netrin-1 is an innate immune system resolvent that can induce tissue-specific regeneration programs and promote organ recovery [52] (Figure 2[ 4 …”

“…As mentioned above, Schlegel et al demonstrated that netrin-1 increases the regeneration capacity following hepatic IR injury. This was associated with improved liver repair via the stimulation of proresolving lipid mediators (SPMs) and the generation of hepatic growth factors [52].…”