B-cells expressing NgR1 and NgR3 are localized to EAE-induced inflammatory infiltrates and are stimulated by BAFF

Bakhuraysah, Maha; Theotokis, Paschalis; Lee, Jae Young; Alrehaili, Amani A.; Aui, Peimun; Figgett, William A.; Azari, Michael F.; Abou-Afech, John-Paul; Mackay, Fabienne; Siatskas, Christopher; Alderuccio, Frank; Strittmatter, Stephen M.; Grigoriadis, Nikolaos; Petratos, Steven

doi:10.1038/s41598-021-82346-6

Cited by 16 publications

(31 citation statements)

References 65 publications

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“…In the cerebellum, the proinflammatory cytokines IL1β and IL6 were reduced in Fgfr1 ind−/− mice at day 62 p.i. Cytokines play a key role in recruiting activated immune cells into the CNS [40][41][42]. IL1β plays a role in neuronal degeneration via p53-mediated apoptosis of neurons [43].…”

Section: Discussionmentioning

confidence: 99%

Oligodendrocyte-Specific Deletion of FGFR1 Reduces Cerebellar Inflammation and Neurodegeneration in MOG35-55-Induced EAE

Rajendran

Giraldo-Velásquez

et al. 2021

IJMS

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Multiple sclerosis (MS) is a chronic inflammatory and degenerative disease of the central nervous system (CNS). MS commonly affects the cerebellum causing acute and chronic symptoms. Cerebellar signs significantly contribute to clinical disability, and symptoms such as tremor, ataxia, and dysarthria are difficult to treat. Fibroblast growth factors (FGFs) and their receptors (FGFRs) are involved in demyelinating pathologies such as MS. In autopsy tissue from patients with MS, increased expression of FGF1, FGF2, FGF9, and FGFR1 was found in lesion areas. Recent research using mouse models has focused on regions such as the spinal cord, and data on the expression of FGF/FGFR in the cerebellum are not available. In recent EAE studies, we detected that oligodendrocyte-specific deletion of FGFRs results in a milder disease course, less cellular infiltrates, and reduced neurodegeneration in the spinal cord. The objective of this study was to characterize the role of FGFR1 in oligodendrocytes in the cerebellum. Conditional deletion of FGFR1 in oligodendrocytes (Fgfr1ind−/−) was achieved by tamoxifen application, EAE was induced using the MOG35-55 peptide. The cerebellum was analyzed by histology, immunohistochemistry, and western blot. At day 62 p.i., Fgfr1ind−/− mice showed less myelin and axonal degeneration compared to FGFR1-competent mice. Infiltration of CD3(+) T cells, Mac3(+) cells, B220(+) B cells and IgG(+) plasma cells in cerebellar white matter lesions (WML) was less in Fgfr1ind−/−mice. There were no effects on the number of OPC or mature oligodendrocytes in white matter lesion (WML). Expression of FGF2 and FGF9 associated with less myelin and axonal degeneration, and of the pro-inflammatory cytokines IL-1β, IL-6, and CD200 was downregulated in Fgfr1ind−/−mice. The FGF/FGFR signaling protein pAkt, BDNF, and TrkB were increased in Fgfr1ind−/−mice. These data suggest that cell-specific deletion of FGFR1 in oligodendrocytes has anti-inflammatory and neuroprotective effects in the cerebellum in the EAE disease model of MS.

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Section: Discussionmentioning

confidence: 99%

Oligodendrocyte-Specific Deletion of FGFR1 Reduces Cerebellar Inflammation and Neurodegeneration in MOG35-55-Induced EAE

Rajendran

Giraldo-Velásquez

et al. 2021

IJMS

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“…It has previously been revealed that there is a correlation between BAFF and Nogo receptor (NgR) signaling complex [75], a member of the leucine rich repeat (LRR) superfamily [76], that binds with high affinity and may potentially function as a BAFF receptor [48,77]. The NgR signaling complex consists of NgR1, the co-receptor LINGO-1 and the neurotrophin receptor p75 (p75NTR) or TROY receptor and it mediates its inhibitory effect against axonal regeneration through binding to Nogo 66 with nanomolar affinity [78][79][80].…”

Section: Ngr Complex Signaling Pathways Interaction With Various Componentsmentioning

confidence: 99%

“…The NgR signaling complex consists of NgR1, the co-receptor LINGO-1 and the neurotrophin receptor p75 (p75NTR) or TROY receptor and it mediates its inhibitory effect against axonal regeneration through binding to Nogo 66 with nanomolar affinity [78][79][80]. This receptor complex binds with myelin associated inhibitory factors (MAIFs), which are myelin-associated glycoprotein (MAG), oligodendrocyte-myelin glycoprotein (OMgp) and Nogo-A and are found on myelin sheath of oligodendrocytes [77,81,82]. Nogo-A is one of the three splice variants (Nogo A, B and C), that have a conserved extracellular region of 66 amino acids [80,83], which is found between two transmembrane helices allowing the molecule to anchor to the oligodendrocyte membrane [81].…”

Section: Ngr Complex Signaling Pathways Interaction With Various Componentsmentioning

confidence: 99%

“…During neuroinflammation it has been demonstrated that NgR1-dependent signaling within spinal cord and optic nerve axons occurs through RhoA-GTP and the phosphorylation of the Rho-associated coiled-coil containing protein kinase 2 (ROCK II) to alter axonal transport and elicit neurodegeneration through downstream phosphorylation of the collapsin response mediator protein 2 (CRMP2) at the threonine 555 site located at its C-terminus [21,87]. Moreover, activation of NgR signaling through the binding of MAIFs present in extracellular myelin debris, can potentiate endogenous inhibitory effects on the maturation of oligodendroglial precursor cells (OPCs) and their recruitment around demyelinated plaques disrupting the remyelination process in progressive MS [77].…”

Section: Ngr Complex Signaling Pathways Interaction With Various Componentsmentioning

confidence: 99%

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Novel contributors to B cell activation during inflammatory CNS demyelination; An oNGOing process

Damianidou¹,

Theotokis²,

Grigoriadis³

et al. 2022

Int. J. Med. Sci.

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Over the past two decades, the development of targeted immunotherapeutics for relapsing-remitting multiple sclerosis has been successfully orchestrated through the efficacious modulation of neuroinflammatory outcomes demonstrated in the experimental autoimmune encephalomyelitis (EAE) model. In this model, the focus of developing immunomodulatory therapeutics has been demonstrated through their effectiveness in modifying the pro-inflammatory Th1 and Th17-dependent neuropathological outcomes of demyelination, oligodendrocytopathy and axonal dystrophy. However, recent successful preclinical and clinical trials have advocated for the significance of B cell-dependent immunopathogenic responses and has led to the development of novel biologicals that target specific B cell phenotypes. In this context, a new molecule, B-cell activating factor (BAFF), has emerged as a positive regulator of B cell survival and differentiation functioning through various signaling pathways and potentiating the activity of various receptor complexes through pleiotropic means. One possible cognate receptor for BAFF includes the Nogo receptor (NgR) and its homologs, previously established as potent inhibitors of axonal regeneration during central nervous system (CNS) injury and disease. In this review we provide current evidence for BAFF-dependent signaling through the NgR multimeric complex, elucidating their association within the CNS compartment and underlying the importance of these potential pathogenic molecular regulators as possible therapeutic targets to limit relapse rates and potentially MS progression.

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“…The soluble BAFF (sBAFF) is formed from the hydrolysis of membrane-type BAFF and can improve the activity of B cells, CD4+T cells, and NK cells to increase the body's immune responses [30]. Three kinds of the receptors of BAFF have been reported, they are B-cell maturation antigen (BCMA), BAFF receptor 3 (BR3), and trans-membrane activator and calcium modulator and cyclophilin ligand interactor (TACI) [2,[31][32][33][34][35][36][37][38][39][40][41]. Although BAFF often functions as a homo-trimer form, a more active BAFF 60-mer has been reported [42].…”

Section: Introductionmentioning

confidence: 99%

Distinct Binding Mode of BAFF antagonist antibodies Belimumab and Tabalumab, analyzed by computer simulation

Sun

Wei

2021

Preprint

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B-cell activating factor (BAFF) can binding to specific receptors and activate signaling pathways associated with B cell activation. Belimumab and tabalumab are anti-BAFF monoclonal antibodies, while belimumab was proved by FDA in 2011 as a targeted therapy for systemic lupus erythematosus (SLE) and showed better clinical effect than tabalumab. The combination modes of BAFF-belimumab complex and BAFF-tabalumab complex were simulated to better understand the reason for the difference of the inhibition effect between belimumab and tabalumab. The structures of belimumab and tabalumab were constructed by homology modeling. The combination mode of BAFF-belimumab complex was analyzed by molecular dynamics simulation, and the combination mode of BAFF-tabalumab complex was analyzed by protein-protein docking after molecular dynamics simulation. Both belimumab and tabalumab contacted with BAFF at the same hydrophobic center which the natural receptors of BAFF bind to. I51, F54, K58 D100, D101, L102, L103, P105 of belimumab heavy chain and R27, Y30, K49, S65 of belimumab light chain contribute to the BAFF-belimumab interaction mainly by hydrogen bond, salt bridge and hydrophobic effect. More important, Belimumab could contact with L83 of BAFF and produced a steric hindrance with the adjacent BAFF trimers, while tabalumab could not. Belimumab had better clinical effect than tabalumab mainly because it could bind to L83 of BAFF and affect the formation of BAFF 60-mer, in addition to inhibition of the interaction of BAFF with its receptors.

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B-cells expressing NgR1 and NgR3 are localized to EAE-induced inflammatory infiltrates and are stimulated by BAFF

Cited by 16 publications

References 65 publications

Oligodendrocyte-Specific Deletion of FGFR1 Reduces Cerebellar Inflammation and Neurodegeneration in MOG35-55-Induced EAE

Oligodendrocyte-Specific Deletion of FGFR1 Reduces Cerebellar Inflammation and Neurodegeneration in MOG35-55-Induced EAE

Novel contributors to B cell activation during inflammatory CNS demyelination; An oNGOing process

Distinct Binding Mode of BAFF antagonist antibodies Belimumab and Tabalumab, analyzed by computer simulation

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