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 3

CLRc regulates expression of Mcl and Mincle in monocytes and macrophages.

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CLRc regulates expression of Mcl and Mincle in monocytes and macrophages...
(A) Expression of Mcl and Mincle assessed by microarray in spleens of (DA × PVG) × DA backcrossed rats subjected to EAE, affected (n = 95, score ≥1) and nonaffected (n = 51, score 0). (B) Gene expression in DA (n = 6) and CLRc (n = 6) spleens determined by qPCR (representative of 2 experiments). (C) Flow cytometry analysis of cells isolated from blood and spinal cord of naive DA (n = 5) and CLRc (n = 5), as well as DA (n = 7) and CLRc (n = 6) rats on day 13 p.i. assessing Mcl and Mincle protein expression by mean fluorescence intensity (MFI) (representative of 2 experiments). Ly, lymphocyte; Mi, microglia; Mo/Ma, monocyte/macrophage; Gr, granulocyte. (D) qPCR analysis of Mcl and Mincle expression in BMMas and MoDCs (BM-APCs) derived in vitro and meninges from naive and 7-day-p.i. DA (n = 4) and CLRc (n = 4) rats (representative of 2 experiments). (E) Immunofluorescent staining of rat spinal cord 11 days p.i. Representative images of staining for Mcl, Mincle, and nuclei (DAPI) (original magnification, ×40). Data are presented as the mean ± SEM or box plots with whiskers representing 5th to 95th percentile. All comparisons were analyzed with the Mann-Whitney U test. *P < 0.05; **P < 0.01; ***P < 0.001.