BackgroundMultiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) characterized by damage to the neuronal myelin sheath. One of the key effectors for inflammatory injury is the antigen-presenting cell (APC). The class A scavenger receptor (SRA), constitutively expressed by APCs, such as macrophages and dendritic cells in peripheral tissues and the CNS, was shown to play a role in the phagocytosis of myelin; however, the role of SRA in the development of experimental autoimmune encephalomyelitis (EAE) and autoimmune reaction in the periphery has not yet been studied.MethodsWe investigated EAE progression in wild-type (WT) vs. SRA−/− mice using clinical score measurements and characterized CNS pathology using staining. Furthermore, we assessed SRA role in mediating anti myelin pro-inflammatory response in cell cultures.ResultsWe discovered that EAE progression and CNS demyelination were significantly reduced in SRA−/− mice compared to WT mice. In addition, there was a reduction of infiltrating peripheral immune cells, such as T cells and macrophages, in the CNS lesion of SRA−/− mice, which was associated with reduced astrogliosis. Immunological assessment showed that SRA deficiency resulted in significant reduction of pro-inflammatory cytokines that play a major role in EAE progression, such as IL-2, IFN-gamma, IL-17 and IL-6. Furthermore, we discovered that SRA−/− APCs showed impairments in activation and in their ability to induce pro-inflammatory CD4+ T cell proliferation.ConclusionExpression of SRA on APCs is important for CD4+ T-cells proliferation in EAE mouse model. Further studies of SRA-mediated cellular pathways in APCs may offer useful insights into the development of MS and other autoimmune diseases, providing future avenues for therapeutic intervention.
Inhibition of insulin-degrading enzyme (IDE) is a possible target for treating diabetes. However, it has not yet evolved into a medical intervention, mainly because most developed inhibitors target the zinc in IDE's catalytic site, potentially causing toxicity to other essential metalloproteases. Since IDE is a cellular receptor for the varicella-zoster virus (VZV), we constructed a VZV-based inhibitor. We computationally characterized its interaction site with IDE showing that the peptide specifically binds inside IDE's central cavity, however, not in close proximity to the zinc ion. We confirmed the peptide's effective inhibition on IDE activity in vitro and showed its efficacy in ameliorating insulin-related defects in types 1 and 2 diabetes mouse models. In addition, we suggest that inhibition of IDE may ameliorate the pro-inflammatory profile of CD4 + T-cells toward insulin. Together, we propose a potential role of a designed VZV-derived peptide to serve as a selectively-targeted and as an efficient diabetes therapy.
Graft versus host disease (GvHD) remains a limiting factor for successful hematopoietic stem cell transplantation (HSCT). T cells and antigen-presenting cells (APCs) are major components of the hematopoietic G-CSF mobilized peripheral blood cell (MPBC) graft. Here we show that a short incubation (2 h) of MPBCs with hexameric Fas ligand (FasL) selectively induces apoptosis of specific donor T cell subsets and APCs but not of CD34 + cells. FasL treatment preferentially induces apoptosis in mature T cell subsets which express high levels of Fas (CD95), such as T stem cell memory, T central memory, and T effector memory cells, as well as T H 1 and T H 17 cells. Anti-CD3/CD28 stimulated T cells derived from FasL-treated-MPBCs express lower levels of CD25 and secrete lower levels of IFN-γ as compared to control cells not treated with FasL. FasL treatment also induces apoptosis of transitional, naïve, memory and plasmablastoid B cells leading to a reduction in their numbers in the graft and following engraftment in transplanted mice. Most importantly, ex vivo treatment of MPBCs with FasL prior to transplant in conditioned NOD-scid IL2Rγ null (NSG) mice prevented GvHD while preserving graft versus leukemia (GvL) effects, and leading to robust stem cell engraftment.
It has been suggested that extracellular alpha synuclein (αSyn) can mediate neuroinflammation in Parkinson’s disease, and that αSyn affects B‐cell maturation. However, the function of αSyn in T cells is poorly understood. We hypothesized that αSyn can affect CD4+ T‐cell proliferation and activity. We found that αSyn deficiency exacerbates disease progression in 8 weeks old C57BL6/J EAE‐induced mice, and that αSyn‐deficient CD4+ T cells have increased pro‐inflammatory response to myelin antigen relative to wild‐type cells, as measured by cytokine secretion of interleukin IL‐17 and interferon gamma. Furthermore, expression of αSyn on a background of αSyn knockout mitigates the inflammatory responses in CD4+ T cells. We discovered that elevated levels of Nurr1, a transcription factor belonging to the orphan nuclear receptor family, are associated with the pro‐inflammatory profile of αSyn‐deficient CD4+ T cells. In addition, we demonstrated that silencing of Nurr1 expression using an siRNA reduces IL‐17 levels and increases the levels of IL‐10, an anti‐inflammatory cytokine. Study of αSyn‐mediated cellular pathways in CD4+ T cells may provide useful insights into the development of pro‐inflammatory responses in immunity, providing future avenues for therapeutic intervention. image
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.