CCL21-CCR7 blockade prevents neuroinflammation and degeneration in Parkinson’s disease models
Abstract Parkinson’s disease (PD) is a progressive degenerative disease of the central nervous system associated with neuroinflammation and microglial cell activation. Chemokine signaling regulates neuron-glia communication and triggers a microglial inflammatory profile. Herein, we identified the ne...
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BMC
2025-02-01
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| Series: | Journal of Neuroinflammation |
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| Online Access: | https://doi.org/10.1186/s12974-024-03318-x |
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| author | Felipe Saceanu Leser Flavio de Souza Júnyor Iohanna Bianca Pagnoncelli Anna Beatriz Delgado Isabelle Medeiros Ana Clara Campanelli Nóbrega Brenda da Silva Andrade Maiara Nascimento de Lima Nícolas Emanoel da Silva Laurent Jacob Kevin Boyé Luiz Henrique Medeiros Geraldo Alessandra Mendonça Teles de Souza Tatiana Maron-Gutierrez Hugo Castro-Faria-Neto Cristian Follmer Carolina Braga Gilda Angela Neves Anne Eichmann Luciana Ferreira Romão Flavia Regina Souza Lima |
| author_facet | Felipe Saceanu Leser Flavio de Souza Júnyor Iohanna Bianca Pagnoncelli Anna Beatriz Delgado Isabelle Medeiros Ana Clara Campanelli Nóbrega Brenda da Silva Andrade Maiara Nascimento de Lima Nícolas Emanoel da Silva Laurent Jacob Kevin Boyé Luiz Henrique Medeiros Geraldo Alessandra Mendonça Teles de Souza Tatiana Maron-Gutierrez Hugo Castro-Faria-Neto Cristian Follmer Carolina Braga Gilda Angela Neves Anne Eichmann Luciana Ferreira Romão Flavia Regina Souza Lima |
| author_sort | Felipe Saceanu Leser |
| collection | DOAJ |
| description | Abstract Parkinson’s disease (PD) is a progressive degenerative disease of the central nervous system associated with neuroinflammation and microglial cell activation. Chemokine signaling regulates neuron-glia communication and triggers a microglial inflammatory profile. Herein, we identified the neuronal chemokine CCL21 as a major cause of microglial cell imbalance through the CCR7 receptor pathway with therapeutic implications for PD. In humans, we found that CCL21 transcript expression was increased in dopaminergic neurons (DANs) of the substantia nigra in PD patients. CCL21 and CCR7 expressions were spatially associated with brain regional vulnerability to synucleinopathies, as well as with the expression of microglial activation, neuroinflammation, and degeneration-related genes. Also, in mouse models of PD, we showed that CCL21 was overexpressed in DANs in vivo and in vitro. Mechanistically, neuronal CCL21 was shown to regulate microglial cell migration, proliferation, and activation in a CCR7-dependent manner through both canonical (PI3K/AKT) and non-canonical (ERK1/2/JNK) signaling pathways. Finally, we demonstrated that navarixin, a clinically relevant chemokine inhibitor with high affinity for the CCR7 receptor, could block CCL21 effects on microglia and prevent neurodegeneration and behavioral deficits in two mouse models of PD induced with either α-synuclein oligomers (αSynO) or 3,4-dihydroxyphenylacetaldehyde (DOPAL). Altogether, our data indicate that navarixin blocks CCL21/CCR7-mediated neuron-microglia communication and could be used as a therapeutic strategy against PD. Graphical Abstract |
| format | Article |
| id | doaj-art-e858b64910c942708a8dc80547d7bbdb |
| institution | Kabale University |
| issn | 1742-2094 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj-art-e858b64910c942708a8dc80547d7bbdb2025-02-09T12:48:09ZengBMCJournal of Neuroinflammation1742-20942025-02-0122112310.1186/s12974-024-03318-xCCL21-CCR7 blockade prevents neuroinflammation and degeneration in Parkinson’s disease modelsFelipe Saceanu Leser0Flavio de Souza Júnyor1Iohanna Bianca Pagnoncelli2Anna Beatriz Delgado3Isabelle Medeiros4Ana Clara Campanelli Nóbrega5Brenda da Silva Andrade6Maiara Nascimento de Lima7Nícolas Emanoel da Silva8Laurent Jacob9Kevin Boyé10Luiz Henrique Medeiros Geraldo11Alessandra Mendonça Teles de Souza12Tatiana Maron-Gutierrez13Hugo Castro-Faria-Neto14Cristian Follmer15Carolina Braga16Gilda Angela Neves17Anne Eichmann18Luciana Ferreira Romão19Flavia Regina Souza Lima20Laboratory of Glial Cell Biology, Biomedical Sciences Institute, Universidade Federal do Rio de JaneiroLaboratory of Glial Cell Biology, Biomedical Sciences Institute, Universidade Federal do Rio de JaneiroLaboratory of Glial Cell Biology, Biomedical Sciences Institute, Universidade Federal do Rio de JaneiroLaboratory of Neurobiology Applied to Biomedicine, Biomedical Sciences Institute, Universidade Federal do Rio de JaneiroLaboratory of Neurobiology Applied to Biomedicine, Biomedical Sciences Institute, Universidade Federal do Rio de JaneiroLaboratory of Glial Cell Biology, Biomedical Sciences Institute, Universidade Federal do Rio de JaneiroLaboratory of Molecular Pharmacology, Biomedical Sciences Institute, Universidade Federal do Rio de JaneiroLaboratory of Immunopharmacology, Oswaldo Cruz Institute, Oswaldo Cruz FoundationLaboratory Molecular Modeling & QSAR, Pharmaceutical Sciences Department, Universidade Federal do Rio de JaneiroInstitut National de la Santé et de la Recherche Médicale (INSERM), Paris Cardiovascular Research Center (PARCC)Institut National de la Santé et de la Recherche Médicale (INSERM), Paris Cardiovascular Research Center (PARCC)Laboratory of Glial Cell Biology, Biomedical Sciences Institute, Universidade Federal do Rio de JaneiroLaboratory Molecular Modeling & QSAR, Pharmaceutical Sciences Department, Universidade Federal do Rio de JaneiroLaboratory of Immunopharmacology, Oswaldo Cruz Institute, Oswaldo Cruz FoundationLaboratory of Immunopharmacology, Oswaldo Cruz Institute, Oswaldo Cruz FoundationLaboratory of Physical Chemistry of Proteins and Peptides (Lafipp), Chemistry Department, Universidade Federal do Rio de JaneiroNúcleo Multidisciplinar de Pesquisas em Biologia, NUMPEX-Bio, Universidade Federal do Rio de JaneiroLaboratory of Molecular Pharmacology, Biomedical Sciences Institute, Universidade Federal do Rio de JaneiroInstitut National de la Santé et de la Recherche Médicale (INSERM), Paris Cardiovascular Research Center (PARCC)Laboratory of Neurobiology Applied to Biomedicine, Biomedical Sciences Institute, Universidade Federal do Rio de JaneiroLaboratory of Glial Cell Biology, Biomedical Sciences Institute, Universidade Federal do Rio de JaneiroAbstract Parkinson’s disease (PD) is a progressive degenerative disease of the central nervous system associated with neuroinflammation and microglial cell activation. Chemokine signaling regulates neuron-glia communication and triggers a microglial inflammatory profile. Herein, we identified the neuronal chemokine CCL21 as a major cause of microglial cell imbalance through the CCR7 receptor pathway with therapeutic implications for PD. In humans, we found that CCL21 transcript expression was increased in dopaminergic neurons (DANs) of the substantia nigra in PD patients. CCL21 and CCR7 expressions were spatially associated with brain regional vulnerability to synucleinopathies, as well as with the expression of microglial activation, neuroinflammation, and degeneration-related genes. Also, in mouse models of PD, we showed that CCL21 was overexpressed in DANs in vivo and in vitro. Mechanistically, neuronal CCL21 was shown to regulate microglial cell migration, proliferation, and activation in a CCR7-dependent manner through both canonical (PI3K/AKT) and non-canonical (ERK1/2/JNK) signaling pathways. Finally, we demonstrated that navarixin, a clinically relevant chemokine inhibitor with high affinity for the CCR7 receptor, could block CCL21 effects on microglia and prevent neurodegeneration and behavioral deficits in two mouse models of PD induced with either α-synuclein oligomers (αSynO) or 3,4-dihydroxyphenylacetaldehyde (DOPAL). Altogether, our data indicate that navarixin blocks CCL21/CCR7-mediated neuron-microglia communication and could be used as a therapeutic strategy against PD. Graphical Abstracthttps://doi.org/10.1186/s12974-024-03318-xParkinson`s diseaseNeuroinflammationMicrogliaChemokine signalingCCL21-CCR7 pathwayDOPAL |
| spellingShingle | Felipe Saceanu Leser Flavio de Souza Júnyor Iohanna Bianca Pagnoncelli Anna Beatriz Delgado Isabelle Medeiros Ana Clara Campanelli Nóbrega Brenda da Silva Andrade Maiara Nascimento de Lima Nícolas Emanoel da Silva Laurent Jacob Kevin Boyé Luiz Henrique Medeiros Geraldo Alessandra Mendonça Teles de Souza Tatiana Maron-Gutierrez Hugo Castro-Faria-Neto Cristian Follmer Carolina Braga Gilda Angela Neves Anne Eichmann Luciana Ferreira Romão Flavia Regina Souza Lima CCL21-CCR7 blockade prevents neuroinflammation and degeneration in Parkinson’s disease models Journal of Neuroinflammation Parkinson`s disease Neuroinflammation Microglia Chemokine signaling CCL21-CCR7 pathway DOPAL |
| title | CCL21-CCR7 blockade prevents neuroinflammation and degeneration in Parkinson’s disease models |
| title_full | CCL21-CCR7 blockade prevents neuroinflammation and degeneration in Parkinson’s disease models |
| title_fullStr | CCL21-CCR7 blockade prevents neuroinflammation and degeneration in Parkinson’s disease models |
| title_full_unstemmed | CCL21-CCR7 blockade prevents neuroinflammation and degeneration in Parkinson’s disease models |
| title_short | CCL21-CCR7 blockade prevents neuroinflammation and degeneration in Parkinson’s disease models |
| title_sort | ccl21 ccr7 blockade prevents neuroinflammation and degeneration in parkinson s disease models |
| topic | Parkinson`s disease Neuroinflammation Microglia Chemokine signaling CCL21-CCR7 pathway DOPAL |
| url | https://doi.org/10.1186/s12974-024-03318-x |
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