C-type lectin receptors Mcl and Mincle control development of multiple sclerosis-like neuroinflammation
Marie N'diaye1, Susanna Brauner1, Sevasti Flytzani1
1Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
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.
Insights
C-type lectin receptors (CLRs), Mcl and Mincle, are implicated in experimental autoimmune encephalomyelitis (EAE), a multiple sclerosis (MS) model. Targeting the Mcl/Mincle pathway may offer new therapeutic strategies for MS.
Area of Science:
- Immunology
- Neuroscience
- Pathology
Background:
- Pattern recognition receptors (PRRs) are vital for immunity but their role in autoimmune diseases remains unclear.
- C-type lectin receptors (CLRs) are a class of PRRs involved in immune responses.
- Experimental autoimmune encephalomyelitis (EAE) serves as a model for multiple sclerosis (MS).
Purpose of the Study:
- To investigate the role of Mcl and Mincle in the pathogenesis of EAE.
- To explore the potential of the Mcl/Mincle pathway as a therapeutic target for MS.
Main Methods:
- Utilized congenic rats with reduced Mcl and Mincle expression on myeloid cells to assess EAE incidence.
- Performed in vivo silencing of Mcl and Mincle and blockade of their ligand SAP130.
- Examined Mcl and Mincle expression in brain lesions of MS patients and analyzed peripheral blood mononuclear cell responses.
Main Results:
- Congenic rats with lower Mcl/Mincle levels showed significantly reduced EAE incidence.
- Silencing Mcl/Mincle or blocking SAP130 impaired T cell recruitment and pathogenic Th17/GM-CSF phenotype development in the CNS.
- MCL- and MINCLE-expressing cells were found in MS brain lesions, with pathway upregulation and increased cellular response observed in MS patients.
Conclusions:
- Mcl and Mincle play a critical role in the pathogenesis of EAE, a model for MS.
- The Mcl/Mincle signaling pathway is implicated in T cell-mediated autoimmunity within the central nervous system.
- Targeting the MCL/MINCLE pathway presents a potential therapeutic strategy for multiple sclerosis.
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