C-type lectin receptors Mcl and Mincle control development of multiple sclerosis–like neuroinflammation
Marie N’diaye, … , Andre O. Guerreiro-Cacais, Maja Jagodic
Marie N’diaye, … , Andre O. Guerreiro-Cacais, Maja Jagodic
Published February 3, 2020; First published November 14, 2019
Citation Information: J Clin Invest. 2020;130(2):838-852. https://doi.org/10.1172/JCI125857.
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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 1

CLRc rats are protected from EAE in a peripheral immune cell–dependent manner.

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CLRc rats are protected from EAE in a peripheral immune cell–dependent m...
Homozygous (CLRc) and heterozygous (Het) congenic rats and their littermate DA controls were immunized with MOG and followed for signs of disease. (A) Clinical signs of EAE and disease parameters in DA littermate controls (n = 18), Het (n = 19), and CLRc rats (n = 9) (representative of 3 experiments). For EAE incidence, the upper dotted bars represent unaffected rats, whereas the lower plain bars represent affected rats. (B) Histopathological analysis of spinal cord (SC) on day 29. Left: Representative images of H&E and Luxol fast blue (LB) staining (original magnification, ×40). Right: Quantification of inflammation and demyelination for DA (n = 9), Het (n = 8), and CLRc rats (n = 9). (C and D) Lethally irradiated rats were transplanted with bone marrow (BM) from donor animals, reconstituted for 2 months, and then immunized with MOG. Clinical signs of EAE and disease parameters were assessed in (C) DA or CLRc recipient rats transplanted with DA-GFP BM (DA-GFP → DA [n = 8] or DA-GFP → CLRc [n = 8]) and (D) DA-GFP recipients transplanted with DA or CLRc BM (CLRc → DA-GFP [n = 8] and DA → DA-GFP [n = 7]). 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), Kruskal-Wallis test with Dunn’s multiple-comparisons test (A [for average, cumulative, and max EAE score] and B), unpaired 2-tailed t test (C and D, for AUC of clinical EAE and weight change), Mann-Whitney U test (C and D, for average, cumulative, and max EAE score), and χ2 test (A, C, and D, for EAE incidence). *P < 0.05; **P < 0.01; ***P < 0.001.