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 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 4

Attenuated response to Mcl/Mincle stimulation in CLRc BMMas resulting in altered CD4+ T cell extravasation and activation.

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Attenuated response to Mcl/Mincle stimulation in CLRc BMMas resulting in...
(A) Bone marrow–derived macrophages (BMMas) from DA (n = 4) and CLRc (n = 4) rats were stimulated with receptor-specific ligands (TDM and TDB) for 18 hours (representative of 3 experiments). Genes downstream of the Mcl/Mincle pathway were analyzed by qPCR. (B) MOG-specific CD4+ effector cells were reactivated for 4 days with DA (n = 6) or CLRc (n = 6) BMMas at a ratio of 40:1 (T cell/BMMa) in the presence of MOG peptide. Flow cytometry analysis of CD4+ T cell assessing cytokine production and proliferation (representative of 2 experiments). (C) Transendothelial extravasation of MOG-specific CD4+ effector cells toward DA (n = 4) or CLRc (n = 4) BMMas. Flow cytometry analysis of CD4+ T cell assessing transmigration (representative of 2 experiments). (D) Adoptive transfer of GFP+ MOG-specific CD4+ effector cells injected i.v. into DA (n = 7) or CLRc (n = 7) recipients 6 days p.i. (representative of 2 experiments). Characterization of proliferation and cytokine production in both GFP– as well as GFP+ infiltrating cells isolated from spinal cord on day 13 p.i. stimulated in vitro with PMA/ionomycin/brefeldin A for 5 hours. Data are presented as the mean ± SEM. All comparisons were analyzed with the Mann-Whitney U test. *P < 0.05; **P < 0.01.