Antibody blockade of CLEC12A delays EAE onset and attenuates disease severity by impairing myeloid cell CNS infiltration and restoring positive immunity
| Autor: | Servio H. Ramirez, Divya Sagar, Ramila Philip, Allison M. Andrews, Xiaofang Huang, Prakash S. Nagarkatti, Jürgen Ruland, Narendra P. Singh, Mitzi Nagarkatti, Pooja Jain, Zafar K. Khan, Konstantin Neumann, Rashida Ginwala |
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| Rok vydání: | 2017 |
| Předmět: |
Central Nervous System
0301 basic medicine Encephalomyelitis Autoimmune Experimental Myeloid Science Protein Tyrosine Phosphatase Non-Receptor Type 11 CCL2 Blood–brain barrier Models Biological Severity of Illness Index Article Mice 03 medical and health sciences 0302 clinical medicine Recurrence Lectins Blocking antibody medicine Animals Lectins C-Type Myeloid Cells Antibodies Blocking Chemokine CCL2 Neuroinflammation Mice Knockout Multidisciplinary biology Protein Tyrosine Phosphatase Non-Receptor Type 6 Multiple sclerosis Experimental autoimmune encephalomyelitis Immunity Transendothelial and Transepithelial Migration Dendritic Cells medicine.disease 3. Good health Phenotype 030104 developmental biology medicine.anatomical_structure Receptors Mitogen Immunology biology.protein Medicine Endothelium Vascular Antibody 030217 neurology & neurosurgery Protein Binding Signal Transduction |
| Zdroj: | Scientific Reports, Vol 7, Iss 1, Pp 1-16 (2017) Scientific Reports |
| ISSN: | 2045-2322 |
| Popis: | The mechanism of dendritic cells (DCs) recruitment across the blood brain barrier (BBB) during neuroinflammation has been the least explored amongst all leukocytes. For cells of myeloid origin, while integrins function at the level of adhesion, the importance of lectins remains unknown. Here, we identified functions of one C-type lectin receptor, CLEC12A, in facilitating DC binding and transmigration across the BBB in response to CCL2 chemotaxis. To test function of CLEC12A in an animal model of multiple sclerosis (MS), we administered blocking antibody to CLEC12A that significantly ameliorated disease scores in MOG35–55-induced progressive, as well as PLP138–151-induced relapsing-remitting experimental autoimmune encephalomyelitis (EAE) mice. The decline in both progression and relapse of EAE occurred as a result of reduced demyelination and myeloid cell infiltration into the CNS tissue. DC numbers were restored in the spleen of C57BL/6 and peripheral blood of SJL/J mice along with a decreased TH17 phenotype within CD4+ T-cells. The effects of CLEC12A blocking were further validated using CLEC12A knockout (KO) animals wherein EAE disease induction was delayed and reduced disease severity was observed. These studies reveal the utility of a DC-specific mechanism in designing new therapeutics for MS. |
| Databáze: | OpenAIRE |
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