PMID- 34172073 OWN - NLM STAT- MEDLINE DCOM- 20220110 LR - 20220110 IS - 1750-1326 (Electronic) IS - 1750-1326 (Linking) VI - 16 IP - 1 DP - 2021 Jun 25 TI - Key role of the CCR2-CCL2 axis in disease modification in a mouse model of tauopathy. PG - 39 LID - 10.1186/s13024-021-00458-z [doi] LID - 39 AB - BACKGROUND: For decades, dementia has been characterized by accumulation of waste in the brain and low-grade inflammation. Over the years, emerging studies highlighted the involvement of the immune system in neurodegenerative disease emergence and severity. Numerous studies in animal models of amyloidosis demonstrated the beneficial role of monocyte-derived macrophages in mitigating the disease, though less is known regarding tauopathy. Boosting the immune system in animal models of both amyloidosis and tauopathy, resulted in improved cognitive performance and in a reduction of pathological manifestations. However, a full understanding of the chain of events that is involved, starting from the activation of the immune system, and leading to disease mitigation, remained elusive. Here, we hypothesized that the brain-immune communication pathway that is needed to be activated to combat tauopathy involves monocyte mobilization via the C-C chemokine receptor 2 (CCR2)/CCL2 axis, and additional immune cells, such as CD4(+) T cells, including FOXP3(+) regulatory CD4(+) T cells. METHODS: We used DM-hTAU transgenic mice, a mouse model of tauopathy, and applied an approach that boosts the immune system, via blocking the inhibitory Programmed cell death protein-1 (PD-1)/PD-L1 pathway, a manipulation previously shown to alleviate disease symptoms and pathology. An anti-CCR2 monoclonal antibody (alphaCCR2), was used to block the CCR2 axis in a protocol that partially eliminates monocytes from the circulation at the time of anti-PD-L1 antibody (alphaPD-L1) injection, and for the critical period of their recruitment into the brain following treatment. RESULTS: Performance of DM-hTAU mice in short-term and working memory tasks, revealed that the beneficial effect of alphaPD-L1, assessed 1 month after a single injection, was abrogated following blockade of CCR2. This was accompanied by the loss of the beneficial effect on disease pathology, assessed by measurement of cortical aggregated human tau load using Homogeneous Time Resolved Fluorescence-based immunoassay, and by evaluation of hippocampal neuronal survival. Using both multiparametric flow cytometry, and Cytometry by Time Of Flight, we further demonstrated the accumulation of FOXP3(+) regulatory CD4(+) T cells in the brain, 12 days following the treatment, which was absent subsequent to CCR2 blockade. In addition, measurement of hippocampal levels of the T-cell chemoattractant, C-X-C motif chemokine ligand 12 (Cxcl12), and of inflammatory cytokines, revealed that alphaPD-L1 treatment reduced their expression, while blocking CCR2 reversed this effect. CONCLUSIONS: The CCR2/CCL2 axis is required to modify pathology using PD-L1 blockade in a mouse model of tauopathy. This modification involves, in addition to monocytes, the accumulation of FOXP3(+) regulatory CD4(+) T cells in the brain, and the T-cell chemoattractant, Cxcl12. FAU - Ben-Yehuda, Hila AU - Ben-Yehuda H AD - Department of Neurobiology, Weizmann Institute of Science, Rehovot, Israel. FAU - Arad, Michal AU - Arad M AD - Department of Neurobiology, Weizmann Institute of Science, Rehovot, Israel. FAU - Peralta Ramos, Javier Maria AU - Peralta Ramos JM AD - Department of Neurobiology, Weizmann Institute of Science, Rehovot, Israel. FAU - Sharon, Efrat AU - Sharon E AD - Department of Neurobiology, Weizmann Institute of Science, Rehovot, Israel. FAU - Castellani, Giulia AU - Castellani G AD - Department of Neurobiology, Weizmann Institute of Science, Rehovot, Israel. FAU - Ferrera, Shir AU - Ferrera S AD - Department of Neurobiology, Weizmann Institute of Science, Rehovot, Israel. FAU - Cahalon, Liora AU - Cahalon L AD - Department of Neurobiology, Weizmann Institute of Science, Rehovot, Israel. FAU - Colaiuta, Sarah Phoebeluc AU - Colaiuta SP AD - Department of Neurobiology, Weizmann Institute of Science, Rehovot, Israel. FAU - Salame, Tomer-Meir AU - Salame TM AD - Flow Cytometry Unit, Life Science Core Facilities, Weizmann Institute of Science, Rehovot, Israel. FAU - Schwartz, Michal AU - Schwartz M AUID- ORCID: 0000-0003-4015-7507 AD - Department of Neurobiology, Weizmann Institute of Science, Rehovot, Israel. michal.schwartz@weizmann.ac.il. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20210625 PL - England TA - Mol Neurodegener JT - Molecular neurodegeneration JID - 101266600 RN - 0 (Ccl2 protein, mouse) RN - 0 (Ccr2 protein, mouse) RN - 0 (Chemokine CCL2) RN - 0 (Immune Checkpoint Inhibitors) RN - 0 (Receptors, CCR2) SB - IM MH - Animals MH - CD4-Positive T-Lymphocytes/immunology MH - Chemokine CCL2/immunology/*metabolism MH - Disease Models, Animal MH - Immune Checkpoint Inhibitors/pharmacology MH - Mice MH - Mice, Transgenic MH - Monocytes/immunology MH - Receptors, CCR2/immunology/*metabolism MH - Tauopathies/*immunology/*metabolism/pathology PMC - PMC8234631 OTO - NOTNLM OT - CCL2 OT - CCR2 OT - CXCL12 OT - Dementia OT - Immunotherapy OT - Monocytes OT - PD-L1 OT - Regulatory T cells OT - Tauopathy COIS- M.S. is an inventor of the intellectual property that forms the basis for development of PD-L1 immunotherapy for AD. EDAT- 2021/06/27 06:00 MHDA- 2022/01/11 06:00 PMCR- 2021/06/25 CRDT- 2021/06/26 05:29 PHST- 2020/11/19 00:00 [received] PHST- 2021/05/26 00:00 [accepted] PHST- 2021/06/26 05:29 [entrez] PHST- 2021/06/27 06:00 [pubmed] PHST- 2022/01/11 06:00 [medline] PHST- 2021/06/25 00:00 [pmc-release] AID - 10.1186/s13024-021-00458-z [pii] AID - 458 [pii] AID - 10.1186/s13024-021-00458-z [doi] PST - epublish SO - Mol Neurodegener. 2021 Jun 25;16(1):39. doi: 10.1186/s13024-021-00458-z.