CCR7 deficient inflammatory Dendritic Cells are retained in the Central Nervous System

Benjamin D Clarkson,Matyas Sandor,Martin Hsu,Aditya Rayasam,Alec Walker,Zsuzsanna Fabry,Melissa G Harris

doi:10.1038/srep42856

Abstract

Dendritic cells (DC) accumulate in the CNS during neuroinflammation, yet, how these cells contribute to CNS antigen drainage is still unknown. We have previously shown that after intracerebral injection, antigen-loaded bone marrow DC migrate to deep cervical lymph nodes where they prime antigen-specific T cells and exacerbate experimental autoimmune encephalomyelitis (EAE) in mice. Here, we report that DC migration from brain parenchyma is dependent upon the chemokine receptor CCR7. During EAE, both wild type and CCR7−/− CD11c-eYFP cells infiltrated into the CNS but cells that lacked CCR7 were retained in brain and spinal cord while wild type DC migrated to cervical lymph nodes. Retention of CCR7-deficient CD11c-eYFP cells in the CNS exacerbated EAE. These data are the first to show that CD11chigh DC use CCR7 for migration out of the CNS, and in the absence of this receptor they remain in the CNS in situ and exacerbate EAE.

Highlights

CNS autoimmune diseases, including multiple sclerosis (MS), affect more than 2 million individuals worldwide
In order to test whether CCR7 contributes to Dendritic cells (DC) migration from the brain parenchyma to the CLN, we backcrossed B6 congenic DC-reporter mice expressing enhanced yellow fluorescent protein downstream of the CD11c promoter (CD11c-eYFP) with congenic CCR7 deficient (−/−)mice
Using CCR7−/−CD11c-eYFP reporter mice and the parent CD11c-eYFP CCR7 sufficient (+/+) mouse line, we generated DC by culturing bone marrow-derived (BM) cells with GM-cerebral spinal fluid (CSF) and confirmed that CCR7 deficient and sufficient cells were comparable for costimulatory molecule expression and antigen presenting capability (Fig. S1)

Summary

Introduction

CNS autoimmune diseases, including multiple sclerosis (MS), affect more than 2 million individuals worldwide. We have shown that i.c. injected OVA-loaded inflammatory bone marrow-derived (BM)DC express low levels of CCR7 and migrate to deep CLN where they prime OVA-specific T cell responses[11]. This migration could be blocked by pretreatment of BMDC with pertussis toxin, suggesting that it is not passive migration and is rather mediated by G protein-dependent motility found downstream of many chemokine receptors. We have shown that i.c. injection of MOG peptide-loaded BMDC prior to induction of EAE exacerbates disease[12], suggesting that the number of CNS-infiltrating DC is rate-limiting in the initiation of EAE It is still unknown whether the primary role of CNS-infiltrating DC is to transport www.nature.com/scientificreports/. Regulating DC migration out from the inflamed CNS may be a therapeutic target for MS and other chronic neuroinflammatory conditions

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Results

Conclusion