C-type lectin receptors Mcl and Mincle control development of multiple sclerosis–like neuroinflammation
Marie N’diaye, Susanna Brauner, Sevasti Flytzani, Lara Kular, Andreas Warnecke, Milena Z. Adzemovic, Eliane Piket, Jin-Hong Min, Will Edwards, Filia Mela, Hoi Ying Choi, Vera Magg, Tojo James, Magdalena Linden, Holger M. Reichardt, Michael R. Daws, Jack van Horssen, Ingrid Kockum, Robert A. Harris, Tomas Olsson, Andre O. Guerreiro-Cacais, Maja Jagodic
Marie N’diaye, Susanna Brauner, Sevasti Flytzani, Lara Kular, Andreas Warnecke, Milena Z. Adzemovic, Eliane Piket, Jin-Hong Min, Will Edwards, Filia Mela, Hoi Ying Choi, Vera Magg, Tojo James, Magdalena Linden, Holger M. Reichardt, Michael R. Daws, Jack van Horssen, Ingrid Kockum, Robert A. Harris, Tomas Olsson, Andre O. Guerreiro-Cacais, Maja Jagodic
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Research Article Autoimmunity Immunology

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

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.

Authors

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

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Figure 5

CNS-specific Mcl/Mincle silencing, as well as blockage of the endogenous ligand SAP130, protects from EAE.

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CNS-specific Mcl/Mincle silencing, as well as blockage of the endogenous...
(A) MOG-immunized rats injected with Mcl (n = 8), Mincle (n = 8), Mcl/Mincle (n = 8), or scrambled control siRNA (n = 8) i.t. and i.c. at 7, 9, and 12 days p.i. were followed for clinical signs of EAE (representative of 3 experiments). (B) Characterization of proliferation and cytokine production of infiltrating cells isolated from spinal cord on day 12 p.i., stimulated in vitro with PMA/ionomycin/brefeldin A for 5 hours (proliferation and cytokine production) in rats injected with Mcl/Mincle (n = 5) or scrambled control siRNA (n = 6) and (C) quantification of IFN-γ– and IL-17–producing CD4+ T cells (representative of 2 experiments). (D) Clinical signs of EAE and disease parameters in DA rats treated with anti-SAP130 (n = 18) or rabbit IgG isotype control (n = 18) antibody i.t. and i.c. on days 2 and 7 p.i. (2 pooled experiments). Data are presented as the mean ± SEM. The following statistical tests were used: 1-way ANOVA with Dunnett’s multiple-comparisons test (A, for area under the curve [AUC] of clinical EAE and weight change), Mann-Whitney U test (A–D [for average, cumulative, and max EAE score], B, and C), unpaired 2-tailed t test (D, for AUC of clinical EAE and weight change), and χ2 test (A and D, for EAE incidence). *P < 0.05.