Pharmacological prion protein silencing accelerates central nervous system autoimmune disease via T cell receptor signalling

Abstract

The primary biological function of the endogenous cellular prion protein has remained unclear. We investigated its biological function in the generation of cellular immune responses using cellular prion protein gene-specific small interfering ribonucleic acid in vivo and in vitro. Our results were confirmed by blocking cellular prion protein with monovalent antibodies and by using cellular prion protein-deficient and -transgenic mice. In vivo prion protein gene-small interfering ribonucleic acid treatment effects were of limited duration, restricted to secondary lymphoid organs and resulted in a 70% reduction of cellular prion protein expression in leukocytes. Disruption of cellular prion protein signalling augmented antigen-specific activation and proliferation, and enhanced T cell receptor signalling, resulting in zeta-chain-associated protein-70 phosphorylation and nuclear factor of activated T cells/activator protein 1 transcriptional activity. In vivo prion protein gene-small interfering ribonucleic acid treatment promoted T cell differentiation towards pro-inflammatory phenotypes and increased survival of antigen-specific T cells. Cellular prion protein silencing with small interfering ribonucleic acid also resulted in the worsening of actively induced and adoptively transferred experimental autoimmune encephalomyelitis. Finally, treatment of myelin basic protein1–11 T cell receptor transgenic mice with prion protein gene-small interfering ribonucleic acid resulted in spontaneous experimental autoimmune encephalomyelitis. Thus, central nervous system autoimmune disease was modulated at all stages of disease: the generation of the T cell effector response, the elicitation of T effector function and the perpetuation of cellular immune responses. Our findings indicate that cellular prion protein regulates T cell receptor-mediated T cell activation, differentiation and survival. Defects in autoimmunity are restricted to the immune system and not the central nervous system. Our data identify cellular prion protein as a regulator of cellular immunological homoeostasis and suggest cellular prion protein as a novel potential target for therapeutic immunomodulation.

The cellular prion protein in multiple sclerosis: A potential target for neurotherapeutics?

“…These results were also corroborated in another study using a PrP-null mouse, where EAE signs were worsened; siRNA against PrP C also showed a protective effect of PrP C [32]. In contrast, overexpression of PrP to.…”

Endogenous Prion Protein Attenuates Experimentally Induced Colitis

“…18,25 For example, the severity of murine experimental autoimmune encephalomyelitis, a model of mul- tiple sclerosis, was significantly increased in PrP C -deficient mice, 18,25 whereas overexpression of PrP C conferred protection against induction of disease. 19 The increased neuroinflammation observed in PrP C deficiency was attributed to the presence of increased levels of IL-17-producing T cells. 18,25 These observations are interesting in the context of the present study because the cytokine expression profile in the mice lacking Prnp, together with the marked increase in phospho-STAT3, a molecule required for the ontogeny of Th17 cells, would be predicted to favor Th17 cell differentiation.…”

“…For example, PrP C was one of the two most up-regulated proteins during the recovery phase after traumatic brain injury, 14 and the level of PrP C expression is a significant factor not only in determining responses to experimental cerebral ischemia 15 but also in murine models of Alzheimer's disease. 16,17 Furthermore, Prnp deficiency exacerbates neuroinflammation during murine experimental autoimmune encephalomylelitis, 18,19 dysregulates iron and copper homeostasis, 20,21 and sensitizes cells to ischemia and oxidative stress. 3,22 Thus, via molecular mechanism(s) that remain ill defined, PrP C is able to exert cytoprotective functions.…”

“…26,27 Moreover, depletion of PrP C skews T cells toward the helper T cell type 1 (Th1) and type 17 (Th17) phenotypes. 18,19 This is of significance because these lineages produce a variety of proinflammatory cytokines that are up-regulated in the intestinal mucosa in individuals with inflammatory bowel disease. 28 Another possibility is that PrP C functions as an antimicrobial peptide.…”

Neuroprotective Effects of the Cellular Prion Protein in Autoimmune Optic Neuritis

“…It is expressed by T lymphocytes and cells of myeloid lineage, 29 -31 and is thought to have a role in many T-cell physiologic features including activation, 29,30 antigen presentation, 32 phagocytosis, 33 differentiation, and survival. 34 Collectively, the data suggest that PrP C may have multiple roles in autoimmune diseases such as multiple sclerosis. To investigate its po-tential role in both autoimmunity and neuroprotection, the present study used experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis that is associated with optic neuritis in more than 90% of animals.…”