Changes in the BTK/NF-κB signaling pathway and related cytokines in different stages of neuromyelitis optica spectrum disorders

Qiao, Huimin; Mao, Zhuo-feng; Wang, Wei; Chen, Xin; Wang, Suhuan; Fan, Haolong; Zhao, Tianyi; Hou, Huilian; Dong, Mei

doi:10.1186/s40001-022-00723-x

Cited by 7 publications

(4 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“… 73 BTK/NF-κB pathway was found to be activated in NMOSD patients in the acute phase, but not in the remission phase, compared with healthy controls. 70 This provided the preliminary evidence that BTK inhibition could be a potential therapy to ameliorate the pathological progression of NMOSDs. However, the precise mechanisms of BTK involvement are needed to be further confirmed.…”

Section: The Immune-related Mechanisms Of Btk Inhibition In the Centr...mentioning

confidence: 87%

“…68,69 In addition, B cells are also present in meningeal inflammation areas, causing pathological changes in brain cortex. 70,71 BTK inhibition, but not anti-CD20 B-cell depletion, succeeded to eliminate B cells in the meningeal inflammation. 71 Therefore, BTK inhibition, with its selectivity and reversibility, is promising to serve as an alternative MS therapy.…”

Section: Beyond Bcr Signaling Pathwaymentioning

confidence: 94%

See 1 more Smart Citation

The Immunomodulatory Functions of BTK Inhibition in the Central Nervous System

Cao¹,

Wang²,

Zhu³

2022

JIR

View full text Add to dashboard Cite

Bruton's tyrosine kinase (BTK) is a central signaling node in B cells. BTK inhibition has witnessed great success in the treatment of B-cell malignancies. Additionally, in the immune system, BTK is also a prominent component linking a wide variety of immune-related pathways. Therefore, more and more studies attempting to dissect the role of BTK in autoimmune and inflammation progression have emerged in recent years. In particular, BTK expression was also found to be elevated within the central nervous system (CNS) during neuroinflammation. BTK inhibitors are capable of crossing the blood-brain barrier rapidly to modulate B cell functions, attenuate microglial activities and affect NLRP3 inflammasome pathways within the CNS to improve the outcome of diseases. Thus, BTK inhibition appears to be a promising approach to modulate dysregulated inflammation in the CNS and alleviate destruction caused by excessive inflammatory responses. This review will summarize the immunomodulatory mechanisms in which BTK is involved in the development of neurological diseases and discuss the therapeutic potential of BTK inhibition for the treatment of neuroinflammatory pathology.

show abstract

Section: The Immune-related Mechanisms Of Btk Inhibition In the Centr...mentioning

confidence: 87%

Section: Beyond Bcr Signaling Pathwaymentioning

confidence: 94%

The Immunomodulatory Functions of BTK Inhibition in the Central Nervous System

Cao¹,

Wang²,

Zhu³

2022

JIR

View full text Add to dashboard Cite

show abstract

“…However, the regulation of chemokine levels in NMOSD patients is contradictory in the literature. For instance, while one study reported elevated levels of the systemic neutrophil-related chemokine CXCL2 in AQP4-IgG-seropositive patients compared to controls [ 25 ], another study found decreased serum CXCL2 levels [ 22 ]. Our study also found decreased local CXCL2 secretion in retinas treated with NMOSD IgG compared to control IgG.…”

Section: Discussionmentioning

confidence: 99%

“…In particular, chemokines CCL2 and CCL5 have been found to be increased in response to AQP4-IgG treatment in isolated rat astrocyte cultures [ 21 ]. However, the implications for CXCL2 and CXCL10 remain ambiguous, as divergent findings have been reported in the serum of NMOSD patients across various studies [ 22 , 23 , 24 , 25 ]. Although chemokines CCL3 and CCL4 are known to be elevated in the serum of NMOSD patients, their concentrations within the retinal milieu are yet to be explored [ 26 , 27 ].…”

Section: Introductionmentioning

confidence: 99%

NMOSD IgG Impact Retinal Cells in Murine Retinal Explants

Wolf,

Ehinger,

Guempelein

et al. 2023

CIMB

View full text Add to dashboard Cite

Neuromyelitis optica spectrum disorders (NMOSD) are chronic inflammatory diseases of the central nervous system, characterized by autoantibodies against aquaporin-4. The symptoms primarily involve severe optic neuritis and longitudinally extensive transverse myelitis. Although the disease progression is typically relapse-dependent, recent studies revealed retinal neuroaxonal degeneration unrelated to relapse activity, potentially due to anti-aquaporin-4-positive antibodies interacting with retinal glial cells such as Müller cells. In this exploratory study, we analysed the response of mouse retinal explants to NMOSD immunoglobulins (IgG). Mouse retinal explants were treated with purified IgG from patient or control sera for one and three days. We characterized tissue response patterns through morphological changes, chemokine secretion, and complement expression. Mouse retinal explants exhibited a basic proinflammatory response ex vivo, modified by IgG addition. NMOSD IgG, unlike control IgG, increased gliosis and decreased chemokine release (CCL2, CCL3, CCL4, and CXCL-10). Complement component expression by retinal cells remained unaltered by either IgG fraction. We conclude that human NMOSD IgG can possibly bind in the mouse retina, altering the local cellular environment. This intraretinal stress may contribute to retinal degeneration independent of relapse activity in NMOSD, suggesting a primary retinopathy.

show abstract

Effects of intravenous pulse methylprednisolone in neuromyelitis optica during the acute phase

Wang,

Xue,

Wang

et al. 2024

Ann Clin Transl Neurol

View full text Add to dashboard Cite

BackgroundNeuromyelitis optica spectrum disorder (NMOSD) is an anti‐aquaporin 4 (anti‐AQP4) autoantibodies‐mediated idiopathic inflammatory demyelinating disease of the central nervous system. While intravenous pulse methylprednisolone (IVMP) is the recommended initial treatment option for acute onset NMOSD, its therapeutic mechanism remains unclear. We hypothesized that IVMP would reduce the expression of pro‐inflammatory factors and increase the resolution of inflammation in patients with NMOSD.MethodsMendelian randomization (MR) analysis was used to screen meaningful inflammatory and resolution factors for inclusion. Three MR methods with inverse variance weighting (IVW) were primarily used to identify positive results. Interleukin (IL)‐10, IL‐1β, IL‐6, C‐X‐C motif chemokine ligand 12 (CXCL12), and tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL) were screened from 41 inflammatory factors, and resolvin D1 (RvD1), maresin 1 (MaR1), and lipoxin A4 (LXA4) were screened from 6 resolution markers for inclusion. Subsequently, 12 patients with NMOSD were enrolled and treated with IVMP. Serum levels of the aforementioned inflammatory and resolution markers were measured by enzyme‐linked immunosorbent assay before and after IVMP treatment.ResultsHigh levels of TRAIL, CXCL12, and IL‐1β were associated with an increased risk of NMOSD (TRAIL: odds ratio [OR], 1.582; 95% confidence interval [CI], 1.003–2.495; CXCL12: OR, 3.610; 95% CI, 1.011–12.889; IL‐1β: OR, 4.500; 95% CI, 1.129–17.927). High levels of RvD1, MaR1, and LXA4 were associated with a reduced risk of NMOSD (RvD1: OR, 0.725; 95% CI, 0.538–0.976; MaR1: OR, 0.985; 95% CI, 0.970–0.999; LXA4: OR, 0.849; 95% CI, 0.727–0.993). Among patients with NMOSD, serum levels of IL‐6, CXCL12, and TRAIL significantly decreased following IVMP treatment, compared with pretreatment levels, while levels of IL‐1β, LXA4, and MaR1 significantly increased after IVMP treatment (p < 0.05). A significant positive correlation was observed between CXCL12 levels and Expanded Disability Status Scale (EDSS) scores (r = 0.451, p < 0.05).ConclusionSeveral systemic inflammatory regulators associated with the pathogenesis of NMOSD were identified. The protective roles of LXA4 and MaR1 may be indispensable components of glucocorticoid treatment. Therefore, the use of resolution markers may be a potential strategy for improving central nervous system injury in individuals with NMOSD.

show abstract

Changes in the BTK/NF-κB signaling pathway and related cytokines in different stages of neuromyelitis optica spectrum disorders

Cited by 7 publications

References 35 publications

The Immunomodulatory Functions of BTK Inhibition in the Central Nervous System

The Immunomodulatory Functions of BTK Inhibition in the Central Nervous System

NMOSD IgG Impact Retinal Cells in Murine Retinal Explants

Effects of intravenous pulse methylprednisolone in neuromyelitis optica during the acute phase

Contact Info

Product

Resources

About