The Innate Immune Receptor CD14 Mediates Lymphocyte Migration in EAE

Background: Multiple sclerosis is the most common autoimmune disease of the central nervous system in young adults and histopathologically characterized by inflammation, demyelination and gliosis. It is considered as a CD4+ T cell-mediated disease, but also a disease-promoting role of the innate immune system has been proposed, based e.g. on the observation that innate immune receptors modulate disease severity of experimental autoimmune encephalomyelitis. Recent studies of our group provided first evidence for a key role of the innate immune LPS receptor (CD14) in pathophysiology of experimental autoimmune encephalomyelitis. CD14-deficient experimental autoimmune encephalomyelitis mice showed increased clinical symptoms and enhanced infiltration of monocytes and neutrophils in brain and spinal cord. Methods: In the current study, we further investigated the causes of the disease aggravation by CD14-deficiency and examined T cell activation, also focusing on the costimulatory molecules CTLA-4 and CD28, and T cell migration capacity over the blood brain barrier by FACS analysis, in vitro adhesion and transmigration assays. Results: In the results, we observed a significantly increased migration of CD14-deficient lymphocytes across an endothelial monolayer. In contrast, we did not see any differences in expression levels of TCR/CTLA-4 or TCR/CD28 and lymphocyte adhesion to endothelial cells from CD14-deficient compared to wildtype mice. Conclusion: The results demonstrate an important role of CD14 in migration of lymphocytes, and strengthen the importance of innate immune receptors in adaptive immune disorders, such as multiple sclerosis.

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Tim-3 Relieves Experimental Autoimmune Encephalomyelitis by Suppressing MHC-II

Frontiers in Immunology ◽

10.3389/fimmu.2021.770402 ◽

2022 ◽

Vol 12 ◽

Author(s):

Lili Tang ◽

Ge Li ◽

Yang Zheng ◽

Chunmei Hou ◽

Yang Gao ◽

...

Keyword(s):

Multiple Sclerosis ◽

T Cell ◽

Experimental Autoimmune Encephalomyelitis ◽

T Cell Activation ◽

Immune Tolerance ◽

Cell Activation ◽

Autoimmune Encephalomyelitis ◽

Mhc Ii ◽

Experimental Autoimmune

Tim-3, an immune checkpoint inhibitor, is widely expressed on the immune cells and contributes to immune tolerance. However, the mechanisms by which Tim-3 induces immune tolerance remain to be determined. Major histocompatibility complex II (MHC-II) plays a key role in antigen presentation and CD4+T cell activation. Dysregulated expressions of Tim-3 and MHC-II are associated with the pathogenesis of many autoimmune diseases including multiple sclerosis. Here we demonstrated that, by suppressing MHC-II expression in macrophages via the STAT1/CIITA pathway, Tim-3 inhibits MHC-II-mediated autoantigen presentation and CD4+T cell activation. As a result, overexpression or blockade of Tim-3 signaling in mice with experimental autoimmune encephalomyelitis (EAE) inhibited or increased MHC-II expression respectively and finally altered clinical outcomes. We thus identified a new mechanism by which Tim-3 induces immune tolerance in vivo and regulating the Tim-3-MHC-II signaling pathway is expected to provide a new solution for multiple sclerosis treatment.

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Tissue plasminogen activator worsens experimental autoimmune encephalomyelitis by complementary actions on lymphoid and myeloid cell responses

10.21203/rs.3.rs-34631/v1 ◽

2020 ◽

Author(s):

Pauline Hélie ◽

Celia Camacho Toledano ◽

Antonio J Miralles ◽

Maria Cristina Ortega ◽

Virginia Vila del Sol ◽

...

Keyword(s):

Multiple Sclerosis ◽

Experimental Autoimmune Encephalomyelitis ◽

Plasminogen Activator ◽

Tissue Plasminogen Activator ◽

T Cell Activation ◽

Cell Activation ◽

Myeloid Cell ◽

Autoimmune Encephalomyelitis ◽

Tissue Plasminogen ◽

Experimental Autoimmune

Abstract Background Tissue plasminogen activator (tPA) is a serine protease involved in fibrinolysis. It is released by endothelial cells, but also expressed by neurons and glial cells in the central nervous system (CNS). Interestingly, this enzyme also contributes to pathological processes in the CNS such as neuroinflammation by activating microglia and increasing blood-brain-barrier permeability. Nevertheless, its role in the control of adaptive and innate immune response remains poorly understood. Methods tPA effects on myeloid and lymphoid cell response were studied in vivo in the mouse model of multiple sclerosis experimental autoimmune encephalomyelitis and in vitro in splenocytes. Results tPA−/− animals exhibited less severe experimental autoimmune encephalomyelitis than their wild type counterparts. This was accompanied by a reduction in both lymphoid and myeloid cell populations in the spinal cord parenchyma. In parallel, tPA increased T cell activation and proliferation, as well as cytokine production by a protease-dependent mechanism and via plasmin generation. In addition, tPA raised the expression of MHC-II and the co-stimulatory molecule CD80 and CD86 at the surface of dendritic cells and macrophages by an effect dependent of the proteolytic activity of tPA and of the activation of epidermal growth factor receptor. Conclusions Our study provides new insights into the mechanisms responsible for the harmful functions of tPA in multiple sclerosis and its animal models: tPA promotes the proliferation and activation of both lymphoid and myeloid populations by distinct, though complementary, mechanisms.

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