Increased plasma levels of epithelial neutrophil-activating peptide 78/CXCL5 during the remission of Neuromyelitis optica.

BACKGROUND: In neuromyelitis optica (NMO), one of the underlying pathogenic mechanisms is the formation of antigen-antibody complexes which can trigger an inflammatory response by inducing the infiltration of neutrophils in lesions. Epithelial neutrophil-activating peptide 78 (ENA 78), known as Chemokine (C-X-C motif) ligand 5 (CXCL5), belongs to the ELR-CXCL family. It recruits and activates neutrophils. The aim of this study was to evaluate ENA 78, IL-1ß and TNF-α plasma levels in multiple sclerosis (MS) and neuromyelitis optica (NMO) patients. METHODS: ENA 78, IL-1ß and TNF-α plasma levels were detected in 20 healthy controls (HC), 25 MS and 25 NMO patients using MILLIPLEX® map Human High Sensitivity Cytokine/Chemokine Panels. RESULTS: Plasma levels of ENA 78 were significantly higher in NMO patients than in HC (P < 0.001) and MS patients (P < 0.05). The NMO patients showed higher plasma levels of IL-1ß compared with HC (P < 0.01). Further, increased plasma levels of TNF-α were found in the MS (P < 0.05) and NMO patients (P < 0.001). In addition, NMO patients had higher Expanded Disability Status Scale (EDSS) scores compared with MS patients (P < 0.05). EDSS scores were correlated with plasma levels of ENA 78 in NMO patients (P < 0.05). There were no significant correlations between EDSS scores and plasma levels of ENA 78 in MS patients (P > 0.05). CONCLUSIONS: The overproduction of pro-inflammatory cytokines such as IL-1ß and TNF-α during the remission of NMO activates ENA 78, which in turn leads to neutrophil infiltration in lesions. ENA 78 plasma levels were correlated with EDSS scores in NMO patients. Elevated secretion of ENA 78 may be a critical step in neutrophil recruitment during the remission of NMO.

A Case of Chorioretinitis with Retinal Angiomatous Proliferation.

A 48-year-old woman had an acute blurred vision in the right eye immediately after drainage of liver abscess. Her best corrected visual acuity (BCVA) was 8/400; fundus photography suggested the diagnosis of endogenous endophthalmitis with chorioretinitis and vitritis. Due to the bad systemic condition, a systemic antibiotic combined with periocular triamcinolone (TA) was carried out first. Inflammatory cells in the vitreous cavity were decreased after treatment; however, fundus fluorescein angiography (FFA) showed abnormal dilation and leakage of the capillaries and retinal-choroidal anastomose, supporting that there was retinal angiomatous proliferation (RAP). Vitreous interleukin-6 (IL-6) was only slightly elevated; the ratio of interleukin-10 (IL-10) and IL-6 was less than 1, and the etiological test was negative. After receiving intravitreal vancomycin injection combined with periocular TA injection, the patient's BCVA was improved from 16/400 to 20/400 with a reduction in vitreous inflammatory cells. However, the patient's RAP was progressed and her BCVA was dramatically decreased to count finger/30 cm. After intravitreal injection of ranibizumab, the patient's BCVA was 5/400 with a significant shrink in lesions and absorption of hemorrhage, exudation, and fluid. Thus, we suggest that early anti-inflammatory treatment in conjunction with anti-VEGF may achieve a better prognosis in patients with inflammatory retinal angiomatous proliferation (RAP).

Autophagy positively regulates Wnt signaling in mice with diabetic retinopathy.

Diabetic retinopathy (DR) is a microvascular complication of diabetes. Aberrant Wnt signaling activation plays a pathological role in DR. However, the underlying mechanisms of aberrant Wnt signaling in DR remain unknown. Autophagy has been reported to be involved in the pathophysiology of DR. The present study aimed therefore to investigate the regulatory effects of autophagy on Wnt signaling in DR. Wnt signaling was activated in the retina of db/db mice combined with an increase in the expression of the autophagic proteins microtubule-associated protein 1A/1B-light chain 3 and beclin-1 and a decrease in the expression of the autophagic protein P62. Inhibition of autophagy by 3-methyladenin decreased Wnt signaling in diabetic retinas, indicating a potential association between Wnt signaling and autophagy. Rapamycin, an autophagy inducer, upregulated Wnt signaling in the retina of normal C57BL/6J mice. In cultured Müller cells, rapamycin induced autophagy and activated Wnt signaling, while chloroquine, an autophagy inhibitor, inhibited autophagy and downregulated Wnt signaling, suggesting that autophagy could regulate Wnt signaling in mice retina and retinal cells. In summary, this study demonstrated that autophagy may positively regulate Wnt signaling in diabetic retinas, indicating a potential mechanism of Wnt signaling upregulation in DR and a possible novel therapeutic target of DR.

Protective effects of catalpol and rhein in murine experimental autoimmune encephalomyelitis via regulation of T helper (Th) 1, Th2, Th17, and regulatory T cell responses.

OBJECTIVE: To examine the effects of catalpol and rhein on pro- and anti-inflammatory responses in C57BL/6 mice with experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis. METHODS: Female C57BL/6 mice were randomly divided into four groups (n = 30): (a) normal saline control, (b) EAE control, (c) EAE + prednisone acetate (PA, 6 mg/kg), and (d) EAE + catalpol (40 mg/kg) and rhein (5 mg/kg). EAE was induced by injection of myelin oligodendrocyte glycoprotein 35-55 plus pertussis toxin. Treatments were orally administered daily for 40 d. Disease progression and neurological function were assessed using a semi-quantitative scale of tail and limb paralysis. Brains and spinal cords were collected on Days 6, 20, and 40 and assessed for histopathological changes by hematoxylin and eosin staining. Production of interleukin (IL)-2, IL-4, IL-10, and IL-17A protein was measured by enzyme-linked immunosorbent assay. Expression of the T helper (Th)1-, Th2-, Th17-, and regulatory T cell (Treg)-specific transcription factors T-bet, GATA3, ROR-γt, and Foxp3, respectively, were analyzed by quantitative reverse-transcription polymerase chain reaction and western blot analysis. RESULTS: Combination treatment with catalpol and rhein significantly alleviated the clinical disability and neurological dysfunction of mice with EAE. Catalpol and rhein treatment also reduced the infiltration of pro-inflammatory T cells into pathological lesions; significantly increased the expression of the anti-inflammatory factors GATA3, Foxp3, IL-4, and IL-10; and significantly decreased the expression of the pro-inflammatory factors T-bet, ROR-γt, IL-2, and IL-17A. CONCLUSION: Catalpol and rhein reduced the neurological disabilities of mice with EAE, at least in part by rebalancing the pro- and anti-inflammatory environment in the brains and spinal cords.

Upregulation of Bcl-2 and Its Promoter Signals in CD4+ T Cells during Neuromyelitis Optica Remission.

The homeostatic balance between production and elimination of CD4+ T cells in peripheral blood plays an important role in patients with neuromyelitis optica (NMO). The objective of the present study was to evaluate the anti-apoptosis genes Bcl-2 and its promoter signal (nuclear factor kappa-light-chain-enhancer of activated B cells, NFκB) in CD4+ T cells. Healthy subjects (HS, n = 25) and patients with multiple sclerosis (MS) (n = 25) and NMO (n = 30) in remission were consecutively enrolled in this prospective study between May and December 2015. CD4+ T cells were isolated using magnetic beads coated with anti-CD4 monoclonal antibodies, and gene expression of Bcl-2, NFκB, phosphatidylinositol-4, 5-bisphosphate 3-kinase/protein kinase B (PI3K/Akt), and MAP kinase kinase kinase 7 (MAP3K7) was measured by real-time reverse transcription-polymerase chain reaction (rt-PCR). Cytokines of tumor necrosis factor (TNF)-α and interleukin (IL)-1ß were detected using human cytokine multiplex assay. Bcl-2 and NFκB gene expressions were elevated in NMO patients (1.63 ± 0.25; 2.35 ± 0.25) compared with those of HS (0.90 ± 0.11; 1.42 ± 0.22) and/or MS patients (1.03 ± 0.18; 1.55 ± 0.20) (P < 0.05). MAP3K7, but not Akt, was increased in NMO patients (1.23 ± 0.18; 1.56 ± 0.22) (P < 0.01) and was a significant factor related to elevated NFκB gene expressions (P < 0.001). On the other hand, IL-1ß and TNF-α were also detected in the study and the results showed that both were elevated in NMO patients (23.84 ± 1.81; 56.40 ± 2.45) (P < 0.01; P < 0.05, respectively). We propose that MAP3K7 induced by IL-1ß and TNF-α but not Akt promotes NFκB expression and, in turn, prolongs Bcl-2-mediated survival of CD4+ T cells in NMO patients.