C-type lectin receptors Mcl and Mincle control development of multiple sclerosis-like neuroinflammation.

Marie N’Diaye,Eliane Piket,Jack Van Horssen,Susanna Brauner,Robert A Harris,Maja Jagodic,Sevasti Flytzani,Tojo James,Vera Magg,Hoi Ying Choi,Milena Z Adzemovic,Lara Kular,Tomas Olsson,Michael R Daws,Will Edwards,Filia Mela,Andreas Warnecke,Holger M Reichardt,Ingrid Kockum,Magdalena Lindén ,André Ortlieb Guerreiro-Cacais ,Jin Hong Min

doi:10.1172/jci125857

Abstract

Pattern recognition receptors (PRRs) are crucial for responses to infections and tissue damage; however, their role in autoimmunity is less clear. Herein we demonstrate that 2 C-type lectin receptors (CLRs) Mcl and Mincle play an important role in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Congenic rats expressing lower levels of Mcl and Mincle on myeloid cells exhibited a drastic reduction in EAE incidence. In vivo silencing of Mcl and Mincle or blockade of their endogenous ligand SAP130 revealed that these receptors’ expression in the central nervous system is crucial for T cell recruitment and reactivation into a pathogenic Th17/GM-CSF phenotype. Consistent with this, we uncovered MCL- and MINCLE-expressing cells in brain lesions of MS patients and we further found an upregulation of the MCL/MINCLE signaling pathway and an increased response following MCL/MINCLE stimulation in peripheral blood mononuclear cells from MS patients. Together, these data support a role for CLRs in autoimmunity and implicate the MCL/MINCLE pathway as a potential therapeutic target in MS.

Highlights

Multiple sclerosis (MS), a leading cause of neurological disability in young adults, is a chronic inflammatory disease of the central nervous system (CNS) characterized by autoimmune destruction of myelin and subsequent neuroaxonal loss
Using a congenic rat strain with natural variation in expression of C-type lectin receptors (CLRs), we investigated the role of the pattern recognition receptors (PRRs) Mcl and Mincle in EAE pathogenesis, and further examined the findings in human disease
We determined that MCL and MINCLE are expressed in MS lesions, that the signaling pathway is active in peripheral blood mononuclear cells (PBMCs) of CIS and MS patients during relapse compared with controls, and that monocytes from MS patients responded more vigorously to specific receptor stimulation

Summary

Introduction

Multiple sclerosis (MS), a leading cause of neurological disability in young adults, is a chronic inflammatory disease of the central nervous system (CNS) characterized by autoimmune destruction of myelin and subsequent neuroaxonal loss. Antigen-presenting cells (APCs) play a crucial role in the reactivation of CD4+ T cells, which drive the subsequent pathogenic inflammatory responses [2,3,4]. The mechanisms by which T cell fate is determined upon reactivation in the CNS remain poorly understood. A growing body of evidence suggests a role for pattern recognition receptors (PRRs) in autoimmune inflammatory responses [5]. Previous studies have primarily focused on Tolllike receptors (TLRs), showing their potential role in modulating pathogenic disease pathways [6,7,8]; little is known about the role of C-type lectin receptors (CLRs) in autoimmunity and in MS [9]

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