Antibody blockade of CLEC12A delays EAE onset and attenuates disease severity by impairing myeloid cell CNS infiltration and restoring positive immunity

Divya Sagar,Xiaofang Huang,Allison M Andrews,Jürgen Ruland,Rashida Ginwala,Prakash Nagarkatti,Pooja Jain,Mitzi Nagarkatti,Konstantin Neumann,Ramila Philip,Servio H Ramirez,Zafar K Khan,Narendra P Singh

doi:10.1038/s41598-017-03027-x

Abstract

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.

Highlights

The central nervous system (CNS) is structured to be an immune-privileged site to remain protected from detrimental insults that can result in immune-mediated inflammation
Binding of the CLEC12A receptor to the endothelium was demonstrated to be important for monocyte-derived dendritic cells (MDDC)s that are important in development of inflammatory and autoimmune disease[24] and myeloid DCs
Both CD205 (DEC-205) and CD206 (MMR), type I C-type lectin receptors (CLRs) belonging to the mannose receptor (MR) family were expressed on MDDCs and myeloid DCs (mDCs)

Summary

Introduction

The central nervous system (CNS) is structured to be an immune-privileged site to remain protected from detrimental insults that can result in immune-mediated inflammation. In a recent study[3], onset of experimental autoimmune encephalomyelitis (EAE), the mouse model for MS, was shown to coincide with a sudden spike in the number of infiltrating DCs and macrophages in the CNS, the majority of which contained myelin antigen after migration into the CNS. Binding of the CLEC12A receptor to the endothelium was demonstrated to be important for monocyte-derived dendritic cells (MDDC)s that are important in development of inflammatory and autoimmune disease[24] and myeloid DCs (mDCs). This study opens up the prospect of selectively regulating DC entry into the CNS using antibody treatment as a new alternative against disease pathogenesis and propagation in multiple sclerosis and other inflammatory/autoimmune diseases

Methods

Results

Conclusion