Netrin‐1 and multiple sclerosis: a new biomarker for neuroinflammation?

Background and purpose Netrin‐1, an axon guidance protein, reduces serum levels of pro‐inflammatory mediators and stabilizes the blood−brain barrier limiting the entrance of immune cells into the central nervous system. The aim was to investigate its presence in the experimental autoimmune encephalomyelitis ( EAE ) model and in multiple sclerosis ( MS ) patients with and without clinical activity. Methods Netrin‐1 levels were evaluated in EAE mouse tissues. Afterwards, serum netrin‐1 was cross‐sectionally quantified in 90 patients with different MS phenotypes and 30 control subjects. An additional group of 10 relapsing−remitting MS ( RRMS ) patients was longitudinally evaluated throughout a relapse ( RRMS r) with an interval of 60 days. Tumour necrosis factor α ( TNF α), a reference inflammatory cytokine, and netrin‐1 were quantified by enzyme‐linked immunosorbent assay. Results Experimental autoimmune encephalomyelitis mice showed significantly lower netrin‐1 levels and higher TNF α amounts in sera, spinal cord and cerebella than healthy control mice. MS patients showed significantly lower serum netrin‐1 levels than controls (511.62 ± 209.30 and 748.32 ± 103.24 pg/ml, respectively; P ≤ 0.005). The lowest protein levels were found in RRMS r, remaining significantly lower throughout the relapse. TNF α serum concentrations were higher in MS patients compared to controls, and negatively correlated with netrin‐1 levels ( r = −0.3734, P ≤ 0.0001). Conclusions Netrin‐1 decreased in EAE and in MS patients, mainly during relapse, suggesting an anti‐inflammatory role of netrin‐1. Further research should be performed in a larger cohort of patients to validate netrin‐1 as a biomarker of MS inflammatory activity.