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 2

Modulation of T cell activation in the CNS, but not in the periphery, underlies the protective CLRc phenotype.

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Modulation of T cell activation in the CNS, but not in the periphery, un...
Homozygous CLRc rats and littermate DA controls were immunized with MOG and phenotyped during the disease course. Characterization of cells infiltrating draining lymph nodes (dLNs) and the CNS. (A) Frequency of total T cells (CD3), B cells (CD45RA), and CD8+ and CD4+ T cells on day 7 p.i. in dLNs of DA (n = 6–8) and CLRc (n = 6) rats. Frequency of activation markers on CD4+ T cells (representative of 4 experiments). (B) Ki67 expression and cytokine production on day 7 p.i. in CD4+ T cells from dLNs of DA (n = 7–8) and CLRc (n = 5–6) rats following 72-hour in vitro MOG stimulation (representative of 3 experiments). (C) qPCR for Cd62l, Cd11a, Ccr7, and Ccr6 in CD4+ T cells sorted from dLNs of DA (n = 6) and CLRc (n = 6) rats on day 7 p.i. (representative of 2 experiments). (D) Number of infiltrating CD4+ T cells, macrophages/monocytes (Ma/Mo), and granulocytes in spinal cord of naive DA and CLRc rats (n = 12 and n = 12) and at 7 (n = 3 and n = 3), 11 (n = 6 and n = 5), and 13 days p.i. (n = 7 and n = 5) (representative of 2 experiments). (E and F) Characterization of proliferation and cytokine production in infiltrating cells isolated from spinal cord on day 13 p.i. stimulated in vitro with PMA/ionomycin/brefeldin A for 5 hours in CLRc rats (n = 6) and DA rats (n = 6) (representative of 2 experiments). Data are presented as the mean ± SEM. All comparisons were analyzed with the Mann-Whitney U test. *P < 0.05; **P < 0.01.