Year-end Sale % OFF 
Abstract
BackgroundMultiple sclerosis (MS) involves a misdirected immune attack against myelin in the brain and spinal cord, leading to profound neuroinflammation and neurodegeneration. While the mechanisms of disease pathogenesis have been widely studied, the suppression mechanisms that lead to the resolution of the autoimmune response are still poorly understood. Here, we investigated the role of the C-type lectin receptor macrophage galactose-type lectin (MGL), usually expressed on tolerogenic antigen-presenting cells (APCs), as a negative regulator of autoimmune-driven neuroinflammation.MethodsWe used in silico, immunohistochemical, immunofluorescence, quantitative real-time polymerase chain reaction (qRT-PCR) and flow cytometry analysis to explore the expression and functionality of MGL in human macrophages and microglia, as well as in MS post-mortem tissue. In vitro, we studied the capacity of MGL to mediate apoptosis of experimental autoimmune encephalomyelitis (EAE)-derived T cells and mouse CD4+ T cells. Finally, we evaluated in vivo and ex vivo the immunomodulatory potential of MGL in EAE.ResultsMGL plays a critical role in the resolution phase of EAE as MGL1-deficient (Clec10a−/−) mice showed a similar day of onset but experienced a higher clinical score to that of WT littermates. We demonstrate that the mouse ortholog MGL1 induces apoptosis of autoreactive T cells and diminishes the expression of pro-inflammatory cytokines and inflammatory autoantibodies. Moreover, we show that MGL1 but not MGL2 induces apoptosis of activated mouse CD4+ T cells in vitro. In human settings, we show that MGL expression is increased in active MS lesions and on alternatively activated microglia and macrophages which, in turn, induces the secretion of the immunoregulatory cytokine IL-10, underscoring the clinical relevance of this lectin.ConclusionsOur results show a new role of MGL-expressing APCs as an anti-inflammatory mechanism in autoimmune neuroinflammation by dampening pathogenic T and B cell responses, uncovering a novel clue for neuroprotective therapeutic strategies with relevance for in MS clinical applications.
Highlights
Multiple sclerosis (MS) involves a misdirected immune attack against myelin in the brain and spinal cord, leading to profound neuroinflammation and neurodegeneration
Recent studies have revealed that both innate and adaptive immune cells contribute to the pathogenesis and progression of MS and its in vivo model experimental autoimmune encephalomyelitis (EAE) [2], there is little information about the mechanisms involved in the resolution of inflammation during remission, a process that leads to clinical improvement of patients
macrophage galactose-type lectin (MGL) expression in autoimmune neuroinflammation MGL has been shown to have immunoregulatory properties when expressed on tolerogenic antigen-presenting cells (APC) both in autoimmune and cancer settings [8,9,10,11,12,13]
Summary
Multiple sclerosis (MS) involves a misdirected immune attack against myelin in the brain and spinal cord, leading to profound neuroinflammation and neurodegeneration. We investigated the role of the C-type lectin receptor macrophage galactose-type lectin (MGL), usually expressed on tolerogenic antigen-presenting cells (APCs), as a negative regulator of autoimmune-driven neuroinflammation. Recent studies have revealed that both innate and adaptive immune cells contribute to the pathogenesis and progression of MS and its in vivo model experimental autoimmune encephalomyelitis (EAE) [2], there is little information about the mechanisms involved in the resolution of inflammation during remission, a process that leads to clinical improvement of patients. The macrophage galactose-type lectin (MGL; aka Clec10a or CD301) is a member of the C-type lectin receptor (CLR) family [5, 6] This family is composed of a variety of transmembrane and soluble receptors that recognize glycan structures in a Ca2+-dependent manner through a common carbohydrate recognition domain (CRD) and play important roles in both innate and adaptive immune responses [6]. The mouse ortholog MGL1 binds Lewis-A and Lewis-X structures [5, 7]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
