Dopaminergic Toxin 1-Methyl-4-Phenylpyridinium, Proteins α-Synuclein and Glia Maturation Factor Activate Mast Cells and Release Inflammatory Mediators

Kempuraj, Duraisamy; Thangavel, Ramasamy; Yang, Evert; Pattani, Sagar; Zaheer, Smita; Santillan, Donna A.; Santillan, Mark K.; Zaheer, Asgar

doi:10.1371/journal.pone.0135776

Cited by 33 publications

(46 citation statements)

References 74 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…GMF expression level is increased in the CNS of neurodegenerative diseases including EAE (Zaheer et al, 2011b; Thangavel et al, 2012), while GMF knockdown suppresses dopaminergic neuronal loss, glial activation and the expression levels of proinflammatory mediators in the substantia nigra of MPTP-treated animal model of PD (Khan et al, 2015). We have previously reported the expression of GMF in human and mouse mast cells, as GMF was also reported in several extra CNS cells in the body (Kempuraj et al, 2015). GMF could act in an autocrine and paracrine manner in the activation of mast cells in the CNS.…”

Section: Discussionmentioning

confidence: 64%

“…We have previously reported that GMF-induces neurodegeneration by acting on glial cells and neurons (Lim et al, 2004; Zaheer et al, 2008a; Zaheer et al, 2008b; Kempuraj et al, 2013). Additionally, we have also previously shown that GMF activates mast cells to release various inflammatory mediators (Kempuraj et al, 2015; Kempuraj et al, 2016). GMF-induced neuroinflammation leads to the death of neurons in the CNS (Zaheer et al, 2007).…”

Section: Discussionmentioning

confidence: 78%

“…Glia/neurons or BMMCs were also cultured separately in different wells. Glial culture medium and BMMCs culture medium were used in equal (50:50) ratios in the co-culture conditions as reported previously (Kempuraj et al, 2015). These cells were incubated with MPP + or GMF or mast cell proteases as indicated in the results and figure legends.…”

Section: Methodsmentioning

confidence: 99%

“…The cells were incubated with MPP + for 72 h as mentioned above. The BMMCs were collected by centrifugation and processed for the analysis of CD40L expression (n=3) by flow cytometry (BD LSR II with violet laser, BD Biosciences, San Jose, CA) using monoclonal anti-mouse CD40L/TNFSF5 Phycoerythrin conjugated Rat IgG2A antibodies as we have reported previously (Kempuraj et al, 2015). Rat IgG2A isotype control Allophycocyanin conjugated or Rat IgG2A Isotype control Phycoerythrin conjugated were used as isotype matched controls.…”

Section: Methodsmentioning

confidence: 99%

“…Mast cells are implicated in neuroinflammation and in the pathogenesis of PD, Multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE) (Secor et al, 2000; Sayed et al, 2011; Kempuraj et al, 2015). Mast cells are generally co-localized adjacent to glial cells in the brain during neuroinflammatory responses (Kim et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Cross-Talk between Glia, Neurons and Mast Cells in Neuroinflammation Associated with Parkinson’s Disease

Kempuraj

Selvakumar

Zaheer

et al. 2017

J Neuroimmune Pharmacol

Self Cite

View full text Add to dashboard Cite

Parkinson’s disease (PD) is a progressive movement disorder characterized by neuroinflammation and dopaminergic neurodegeneration in the brain. 1-methyl-4-phenylpyridinium (MPP+), a metabolite of the parkinsonian neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces the release of inflammatory mediators from glial cells and neurons. Glia maturation factor (GMF), a brain proinflammatory protein, MPP+, and mast cell-derived inflammatory mediators induce neurodegeneration which eventually leads to PD. However, the precise mechanisms underlying interaction between glial cells, neurons and mast cells in PD still remain elusive. In the present study, mouse bone marrow-derived mast cells (BMMCs) and mouse fetal brain-derived mixed glia/neurons, astrocytes and neurons were incubated with MPP+, GMF and mast cell-derived inflammatory mediators mouse mast cell protease-6 (MMCP-6), MMCP-7 or tryptase/brain-specific serine protease-4 (tryptase/BSSP-4). Inflammatory mediators released from these cells in the culture medium were quantitated by enzyme-linked immunosorbent assay. Neurodegeneration was quantified by measuring total neurite outgrowth following microtubule-associated protein-2 immunocytochemistry. MPP+− induced significant neurodegeneration with reduced total neurite outgrowth. MPP+− induced the release of tryptase/BSSP-4 from the mouse mast cells, and tryptase/BSSP-4 induced chemokine (C-C motif) ligand 2 (CCL2) release from astrocytes and glia/neurons. Overall our results suggest that MPP+, GMF, MMCP-6 or MMCP-7 stimulate glia/neurons, astrocytes or neurons to release CCL2 and matrix metalloproteinase-3. Additionally, CD40L expression is increased in BMMCs after incubation with MPP+ in a co-culture system consisting of BMMCs and glia/neurons. We propose that mast cell interaction with glial cells and neurons during neuroinflammation can be explored as a new therapeutic target for PD.

show abstract

Section: Discussionmentioning

confidence: 64%

Section: Discussionmentioning

confidence: 78%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Cross-Talk between Glia, Neurons and Mast Cells in Neuroinflammation Associated with Parkinson’s Disease

Kempuraj

Selvakumar

Zaheer

et al. 2017

J Neuroimmune Pharmacol

Self Cite

View full text Add to dashboard Cite

show abstract

Mast Cells Release Chemokine CCL2 in Response to Parkinsonian Toxin 1-Methyl-4-Phenyl-Pyridinium (MPP+)

et al. 2015

Self Cite

View full text Add to dashboard Cite

Microglial activation and release of inflammatory cytokines and chemokines are crucial events in neuroinflammation. Microglial cells interact and respond to other inflammatory cells such as T cells and mast cells as well as inflammatory mediators secreted from these cells. Recent studies have shown that neuroinflammation causes and accelerates neurodegenerative disease such as Parkinson’s disease (PD) pathogenesis. 1-methyl-4-phenyl-pyridinium ion (MPP+), the active metabolite of neurotoxin 1- methyl -4- phenyl -1,2,3,6-tetrahydro pyridine (MPTP) activates glial cells and mediate neurodegeneration through release of inflammatory mediators. We have shown that glia maturation factor (GMF) activates glia and induces neuroinflammation and neurodegeneration and that MPP+ activates mast cells and release proinflammatory cytokines and chemokines. The chemokine (C-C motif) ligand 2 (CCL2) levels have been shown to be elevated and play a role in PD pathogenesis. In the present study, we analyzed if MPP+ activates mouse and human mast cells to release chemokine CCL2. Mouse bone marrow-derived mast cells (BMMCs) and human umbilical cord blood-derived cultured mast cells (hCBMCs) were incubated with MPP+ (10 μM) for 24 h and CCL2 levels were measured in the supernatant media by ELISA. MPP+-significantly-induced CCL2 release from BMMCs and hCBMCs. Additionally, GMF overexpression in BMMCs obtained from wild-type mice released significantly more CCL2, while BMMCs obtained from GMF-deficient mice showed less CCL2 release. Further, we show that MPP+-induced CCL2 release was greater in BMMCs-astrocyte co-culture conditions. Uncoupling protein 4 (UCP4) which is implicated in neurodegenerative diseases including PD was detected in BMMCs by immunocytochemistry. Our results suggest that mast cells may play role in PD pathogenesis.

show abstract

Next Generation Precision Medicine: CRISPR-mediated Genome Editing for the Treatment of Neurodegenerative Disorders

Raikwar

Kikkeri

Sakuru

et al. 2019

J Neuroimmune Pharmacol

Self Cite

View full text Add to dashboard Cite

Despite significant advancements in the field of molecular neurobiology especially neuroinflammation and neurodegeneration, the highly complex molecular mechanisms underlying neurodegenerative diseases remain elusive. As a result, the development of the next generation neurotherapeutics has experienced a considerable lag phase. Recent advancements in the field of genome editing offer a new template for dissecting the precise molecular pathways underlying the complex neurodegenerative disorders. We believe that the innovative genome and transcriptome editing strategies offer an excellent opportunity to decipher novel therapeutic targets, develop novel neurodegenerative disease models, develop neuroimaging modalities, develop next-generation diagnostics as well as develop patient-specific precision-targeted personalized therapies to effectively treat neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic lateral sclerosis, Frontotemporal dementia etc. Here, we review the latest developments in the field of CRISPR-mediated genome editing and provide unbiased futuristic insights regarding its translational potential to improve the treatment outcomes and minimize financial burden. However, despite significant advancements, we would caution the scientific community that since the CRISPR field is still evolving, currently we do not know the full spectrum of CRISPR-mediated side effects. In the wake of the recent news regarding CRISPR-edited human babies being born in China, we urge the scientific community to maintain high scientific and ethical standards and utilize CRISPR for developing in vitro disease in a dish model, in vivo testing in nonhuman primates and lower vertebrates and for the development of neurotherapeutics for the currently incurable neurodegenerative disorders.

show abstract

Dopaminergic Toxin 1-Methyl-4-Phenylpyridinium, Proteins α-Synuclein and Glia Maturation Factor Activate Mast Cells and Release Inflammatory Mediators

Cited by 33 publications

References 74 publications

Cross-Talk between Glia, Neurons and Mast Cells in Neuroinflammation Associated with Parkinson’s Disease

Cross-Talk between Glia, Neurons and Mast Cells in Neuroinflammation Associated with Parkinson’s Disease

Mast Cells Release Chemokine CCL2 in Response to Parkinsonian Toxin 1-Methyl-4-Phenyl-Pyridinium (MPP+)

Next Generation Precision Medicine: CRISPR-mediated Genome Editing for the Treatment of Neurodegenerative Disorders

Contact Info

Product

Resources

About