Scrapie pathogenesis: the role of complement C1q in scrapie agent uptake by conventional dendritic cells.
Mice lacking complement components show delayed development of prion disease following peripheral inoculation. The delay could relate to reduced scrapie prion protein (PrP(Sc)) accumulation on follicular dendritic cells (DCs). However conventional DCs (cDCs) play a crucial role in the early pathogenesis of prion diseases and complement deficiency could result in decreased PrP(Sc) uptake by cDCs in the periphery. To explore this possibility, we cultured murine splenic or gut-associated lymph node cDCs with scrapie-infected whole brain homogenate in the presence or absence of complement. Uptake decreased significantly if the serum in the cultures was heat-inactivated. Because heat inactivation primarily denatures C1q, we used serum from C1q(-/-) mice and showed that PrP(Sc) uptake was markedly decreased. PrP(Sc) internalization was saturable and temperature-dependent, suggesting receptor-mediated uptake. Furthermore, uptake characteristics differed from fluid-phase endocytosis. Immunofluorescence showed colocalization of C1q and PrP(Sc), suggesting interaction between these molecules. We evaluated the expression of several complement receptors on cDCs and confirmed that cDCs that take up PrP(Sc) express one of the C1q receptors, calreticulin. Our results show that C1q participates in PrP(Sc) uptake by cDCs, revealing a critical role for cDCs in initial prion capture, an event that takes place before the PrP(Sc) accumulation within the follicular DC network.
Flores-Langarica
Adriana
A
Sir William Dunn School of Pathology, University of Oxford, South Parks Road, OX1 3RE Oxford, UK.
Sebti
Yasmine
Y
Mitchell
Daniel A
DA
Sim
Robert B
RB
MacPherson
Gordon G
GG
D000818:Animals; D001921:Brain / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D018920:Coculture Techniques; D015922:Complement C1q / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D020566:Dendritic Cells, Follicular / Q000276:immunology / Q000378:metabolism; D004705:Endocytosis / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018620:PrPSc Proteins / Q000378:metabolism*; D021381:Protein Transport / Q000276:immunology; D011951:Receptors, Complement / Q000096:biosynthesis; D012608:Scrapie / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology
D018620:PrPSc Proteins; D011951:Receptors, Complement; D015922:Complement C1q