Prion pathogenesis is unaltered in a mouse strain with a permeable blood-brain barrier

Keller, Annika; Абакумова, Ирина; Chincisan, Andra; Reimann, Regina; Avar, Merve; Heinzer, Daniel; Hornemann, Simone; Wagner, Josephin; Kirschenbaum, Daniel S.; Voigt, Fabian F.; Zhu, Chuanbing; Regli, Luca; Helmchen, Fritjof; Aguzzi, Adriano

doi:10.1371/journal.ppat.1007424

Cited by 10 publications

(10 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Mice. Previous studies have shown a negative correlation between pericyte coverage and BBB permeability in the brain (1,2,(17)(18)(19). We therefore asked whether selective leukocyte infiltration into different CNS regions in Pdgfb ret/ret mice can be explained by differences in capillary pericyte coverage in the brain and spinal cord.…”

Section: Spatial Differences In Pericyte Coverage In the Cns Of Pdgfbmentioning

confidence: 92%

Pericytes regulate vascular immune homeostasis in the CNS

Torok

Schreiner

Schaffenrath

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

Pericytes regulate the development of organ-specific characteristics of the brain vasculature such as the blood–brain barrier (BBB) and astrocytic end-feet. Whether pericytes are involved in the control of leukocyte trafficking in the adult central nervous system (CNS), a process tightly regulated by CNS vasculature, remains elusive. Using adult pericyte-deficient mice (Pdgfbret/ret), we show that pericytes limit leukocyte infiltration into the CNS during homeostasis and autoimmune neuroinflammation. The permissiveness of the vasculature toward leukocyte trafficking in Pdgfbret/ret mice inversely correlates with vessel pericyte coverage. Upon induction of experimental autoimmune encephalomyelitis (EAE), pericyte-deficient mice die of severe atypical EAE, which can be reversed with fingolimod, indicating that the mortality is due to the massive influx of immune cells into the brain. Additionally, administration of anti-VCAM-1 and anti–ICAM-1 antibodies reduces leukocyte infiltration and diminishes the severity of atypical EAE symptoms of Pdgfbret/ret mice, indicating that the proinflammatory endothelium due to absence of pericytes facilitates exaggerated neuroinflammation. Furthermore, we show that the presence of myelin peptide-specific peripheral T cells in Pdgfbret/ret;2D2tg mice leads to the development of spontaneous neurological symptoms paralleled by the massive influx of leukocytes into the brain. These findings indicate that intrinsic changes within brain vasculature can promote the development of a neuroinflammatory disorder.

show abstract

Section: Spatial Differences In Pericyte Coverage In the Cns Of Pdgfbmentioning

confidence: 92%

Pericytes regulate vascular immune homeostasis in the CNS

Torok

Schreiner

Schaffenrath

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

show abstract

“…The rate of onset can be accelerated in models in which SLOs are hyperinnervated or where FDCs are juxtaposed to splanchnic nerves (Glatzel et al, 2001). The critical role of retrograde transport of prions has been corroborated via studies showing that disruption of the BBB does not impact pathogenesis (Keller et al, 2018) Conclusions: Can Pathogens Teach Us How to Deliver Therapeutics into the CNS? This review describes CNS entry mechanisms utilized by intracellular and extracellular pathogens.…”

Section: Axonal Transport From Peripheral Neuronsmentioning

confidence: 99%

Mechanisms of Pathogen Invasion into the Central Nervous System

Cain

Salehiniya

Diamond

et al. 2019

Neuron

View full text Add to dashboard Cite

CNS infections continue to rise in incidence in conjunction with increases in immunocompromised populations or conditions that contribute to the emergence of pathogens, such as global travel, climate change, and human encroachment on animal territories. The severity and complexity of these diseases is impacted by the diversity of etiologic agents and their routes of neuroinvasion. In this review, we present historical, clinical, and molecular concepts regarding the mechanisms of pathogen invasion of the CNS. We also discuss the structural components of CNS compartments that influence pathogen entry and recent discoveries of the pathways exploited by pathogens to facilitate CNS infections. Advances in our understanding of the CNS invasion mechanisms of different neurotropic pathogens may enable the development of strategies to control their entry and deliver drugs to mitigate established infections.

show abstract

“…Previous studies have shown a negative correlation between pericyte coverage and BBB permeability in the brain 1, 2, 14–16 . We therefore asked whether selective leukocyte infiltration into the brain in Pdgfb ret/ret (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 88%

Pericytes regulate vascular immune homeostasis in the CNS

Torok

Schreiner

Tsai

et al. 2019

Preprint

Self Cite

View full text Add to dashboard Cite

21Brain endothelium possesses several organ-specific features collectively known as the blood-22 brain barrier (BBB). In addition, trafficking of immune cells in the healthy central nervous 23 system (CNS) is tightly regulated by CNS vasculature. In CNS autoimmune diseases such as 24 multiple sclerosis (MS), these homeostatic mechanisms are overcome by autoreactive 25 2 lymphocyte entry into the CNS causing inflammatory demyelinating immunopathology. 26Previous studies have shown that pericytes regulate the development of organ-specific 27 characteristics of brain vasculature such as the BBB and astrocytic end-feet. Whether pericytes 28 are involved in the control of leukocyte trafficking remains elusive. Using adult, pericyte-29 deficient mice (Pdgfb ret/ret ), we show here that brain vasculature devoid of pericytes shows 30 increased expression of VCAM-1 and ICAM-1, which is accompanied by increased leukocyte 31 infiltration of dendritic cells, monocytes and T cells into the brain, but not spinal cord 32 parenchyma. Regional differences enabling leukocyte trafficking into the brain as opposed to 33 the spinal cord inversely correlate with the pericyte coverage of blood vessels. Upon induction 34 of experimental autoimmune encephalitomyelitis (EAE), pericyte-deficient mice succumb to 35 severe neurological impairment. Treatment with first line MS therapy -fingolimod significantly 36 reverses EAE, indicating that the observed phenotype is due to the massive influx of immune 37 cells into the brain. Furthermore, pericyte-deficiency in mice that express myelin 38 oligodendrocyte glycoprotein peptide (MOG35-55) specific T cell receptor (Pdgfb ret/ret ; 2D2 Tg ) 39 leads to the development of spontaneous neurological symptoms paralleled by massive influx 40 of leukocytes into the brain, suggesting altered brain vascular immune quiescence as a prime 41 cause of exaggerated neuroinflammation. Thus, we show that pericytes indirectly restrict 42 immune cell transmigration into the CNS under homeostatic conditions and during 43 autoimmune-driven neuroinflammation by inducing immune quiescence of brain endothelial 44 cells. 45 46 leukocytes into brain parenchyma, thus contributing to immune privilege of the CNS. BBB 51 function is induced by neural tissue and established by all cell types constituting the 52 neurovascular unit (NVU). Pericytes and mural cells residing on the abluminal side of 53 capillaries and post-capillary venules, regulate several features of the BBB 1, 2 . Studies on Pdgfb 54and Pdgfrb mouse mutants, which exhibit variable pericyte loss, have demonstrated that 55 pericytes negatively regulate endothelial transcytosis which, if not suppressed, leads to 56 increased BBB permeability to plasma proteins 1, 2 . In addition, pericyte-deficient vessels show 57 abnormal astrocyte end-feet polarization 1 . Thus, pericytes regulate several characteristics of 58 brain vasculature during development and in the adult organism 1, 2 . Whether the non-59 permissive properties of brain vasculature to leukocyte traffic...

show abstract

Prion pathogenesis is unaltered in a mouse strain with a permeable blood-brain barrier

Cited by 10 publications

References 30 publications

Pericytes regulate vascular immune homeostasis in the CNS

Pericytes regulate vascular immune homeostasis in the CNS

Mechanisms of Pathogen Invasion into the Central Nervous System

Pericytes regulate vascular immune homeostasis in the CNS

Contact Info

Product

Resources

About