The perivascular presence of neutrophils is one of the primary histological differences between MS and NMO, as reported in NMO patients as well as in mouse and rat models [
2,
7,
26]. Neutrophils are elevated about 20 % in the CSF during remission of NMO patients [
27]. In mouse models of NMO, tissue damage was ameliorated by eliminating neutrophils, whereas increased neutrophils exacerbated tissue damage [
7,
28]. ENA 78 is one of the ELR
+ chemokines specifically inducing neutrophil migration, with the ability to interact with chemokine receptors CXCR1 and CXCR2 [
29,
30]. ENA 78 stimulates neutrophil directed chemotaxis by promoting the intracellular level of elastase and free calcium and inducing neutrophil pro-adhesive activity [
31,
32]. In addition, inhibitors of neutrophil elastase, which are involved in neutrophil migration and neutrophil-mediated tissue damage, have been tested in experimental trials such as Sivelestat [
7,
33‐
35]. Other studies also indicated that the increased ENA 78 amplified the pro-inflammatory cytokine response, which had a direct chemo-attracting effect on neutrophils [
36‐
39]. Therefore, we studied ENA 78 and found that it was dramatically increased in the NMO patients (vs. HC,
P < 0.001; vs. MS,
P < 0.05). Studies proved that ENA 78 was detected in eosinophils, which also aggregated in the NMO lesions [
2,
8,
40], suggesting that eosinophils recruit and activate CXCR2
+ cells such as neutrophils by secreting ENA 78. In the present study, we found that the plasma ENA 78 gradient was correlated with EDSS in NMO patients rather than in MS (
P < 0.05). ENA 78 causes neutrophil aggregation and hyperactivation around the lesions in NMO resulting in demyelination, which is different from the pathophysiological mechanisms of MS. The higher ENA 78 gradient in the blood leads to increased neutrophil aggregation around the lesions, causing severe clinical symptoms.
Although the precise mechanism involving ENA 78 upregulation is not fully understood, factors involved in modulating ENA 78 expression at the transcriptional level and signaling pathways are known in different types of cells [
41‐
43]. Neutrophil chemoattractant chemokines belonging to ELR-CXCL family, especially ENA 78 binding with chemokine receptor CXCR2, mediate the IL-1β driven cell recruitment [
43,
44]. ELR
+ chemokines, including CXCL1, CXCL2 and ENA 78, are triggered by IL-1β [
45‐
47]. IL-1β inducing ENA 78 expression by activating cAMP-response element binding protein (CREB) and NF-kB promoter of ENA 78 is part of the inflammatory response
in vitro and
in vivo [
39,
43,
48‐
50]. IL-1β induces leukocyte rolling, adherence and emigration associated with an increase in kinin B1 receptor mRNA expression, which plays a role in neutrophil recruitment [
44]. This current study results showed that increased IL-1β levels in NMO patients matched the higher ENA 78 levels in the periphery compared with the HC (
P < 0.01). TNF-α, which induces neutrophil influx, exacerbates the lesions in
ex vivo spinal cord and optical nerve of NMO [
28,
51]. Our findings, herein, show that NMO and MS patients had higher plasma levels of TNF-α compared with HC (
P < 0.001;
P < 0.05, respectively). Further, TNF-α potentially increases the adhesion-molecule expression in the brain suggesting a role for anti-TNF therapies in NMO [
8,
52,
53]. The overexpression of IL-1β and TNF-α might be one of the factors inducing severe lesions in NMO, exacerbating the damage mediated by higher ENA 78 levels.