Skin‐derived dendritic cells acquire and degrade the scrapie agent following in vitro exposure

Abstract

Summary The accumulation of the scrapie agent in lymphoid tissues following inoculation via the skin is critical for efficient neuroinvasion, but how the agent is initially transported from the skin to the draining lymph node is not known. Langerhans cells (LCs) are specialized antigen‐presenting cells that continually sample their microenvironment within the epidermis and transport captured antigens to draining lymph nodes. We considered LCs probable candidates to acquire and transport the scrapie agent after inoculation via the skin. XS106 cells are dendritic cells (DCs) isolated from mouse epidermis with characteristics of mature LC cells. To investigate the potential interaction of LCs with the scrapie agent XS106 cells were exposed to the scrapie agent in vitro. We show that XS106 cells rapidly acquire the scrapie agent following in vitro exposure. In addition, XS106 cells partially degrade the scrapie agent following extended cultivation. These data suggest that LCs might acquire and degrade the scrapie agent after inoculation via the skin, but data from additional experiments demonstrate that this ability could be lost in the presence of lipopolysaccharide or other immunostimulatory molecules. Our studies also imply that LCs would not undergo maturation following uptake of the scrapie agent in the skin, as the expression of surface antigens associated with LC maturation were unaltered following exposure. In conclusion, although LCs or DCs have the potential to acquire the scrapie agent within the epidermis our data suggest it is unlikely that they become activated and stimulated to transport the agent to the draining lymph node.

Processing of the Bovine Spongiform Encephalopathy-Specific Prion Protein by Dendritic Cells

“…Moreover, we found that LPS-activated BMDC or BMM showed an accelerated breakdown of PrP bse , suggesting that the process of capture and clearance of PrP bse can be increased following DC maturation or macrophage activation. Our results differ from those of Mohan et al, who showed an inhibition of PrP sc clearance when skin-derived DC were activated by LPS (28). This difference could be due to the prion strain or the subset of DC.…”

“…This difference could be due to the prion strain or the subset of DC. (28). We found that although PrP bse was not detected within the cell culture at 6 days following incubation with BSE prions, infectivity still exists, confirming that the bioassay presents a very superior sensitivity level of infectivity.…”

A Specific Population of Abnormal Prion Protein Aggregates Is Preferentially Taken Up by Cells and Disaggregated in a Strain-Dependent Manner

“…2 and 5 (14,(30)(31)(32)(33)(34), and PrP Sc in scrapie-infected cells can be degraded by cocultivation with dendritic cells (35,36). Our data demonstrate that cells disaggregate PrP Sc within the first 24 h following infection with scrapie.…”

Accelerated Prion Replication in, but Prolonged Survival Times of, Prion-Infected CXCR3−/−Mice

“…Impaired microglial migration in CXCR3 Ϫ/Ϫ mice may well contribute to decreased phagocytosis and consequently less degradation of PrP Sc deposits, because only migratory microglia can be expected to efficiently reach deposits of misfolded protein for subsequent engulfment. A role of phagocytes in uptake and degradation of PrP Sc has been demonstrated in cell cultures (10,11,45) and in prion-infected animals (2,42). Moreover, depletion of microglia from prion-infected organotypic brain slices was shown to promote dramatic increases in PK-resistant PrP Sc and prion infectivity (19).…”