title: Host fibrinogen stably bound to hemozoin rapidly activates monocytes via TLR-4 and CD11b/CD18-integrin: a new paradigm of hemozoin action.
abstract: Natural hemozoin (nHZ), prepared after schizogony, consists of crystalline ferriprotoporphyrin-IX dimers from undigested heme bound to host and parasite proteins and lipids. Phagocytosed nHZ alters important functions of host phagocytes. Most alterations are long-term effects. We show that host fibrinogen (FG) was constantly present (at ~ 1 FG per 25 000 HZ-heme molecules) and stably bound to nHZ from plasma-cultured parasites. FG was responsible for the rapid 100-fold stimulation of reactive oxygen species production and 50-fold increase of TNF and monocyte chemotactic protein 1 by human monocytes. Those effects, starting within minutes after nHZ cell contact, were because of interaction of FG with FG-receptors TLR4 and integrin CD11b/CD18. Receptor blockage by specific mAbs or removal of FG from nHZ abrogated the effects. nHZ-opsonizing IgGs contribute to the stimulatory response but are not essential for FG effects. Immediate increase in reactive oxygen species and TNF may switch on previously described long-term effects of nHZ, largely because of HZ-generated lipo-peroxidation products 15(S,R)-hydroxy-6,8,11,13-eicosatetraenoic acid and 4-hydroxynonenal. The FG/HZ effects mediated by TLR4/integrins represent a novel paradigm of nHZ activity and allow expansion of nHZ effects to nonphagocytic cells, such as endothelia and airway epithelia, and lead to a better understanding of organ pathology in malaria.
authors: Department of Genetics, Biology, and Biochemistry, University of Torino Medical School, Torino, Italy.
authors: Valentina
authors: V
authors: Barrera
authors: Oleksii A
authors: OA
authors: Skorokhod
authors: Denisa
authors: D
authors: Baci
authors: Giuliana
authors: G
authors: Gremo
authors: Paolo
authors: P
authors: Arese
authors: Evelin
authors: E
authors: Schwarzer
mesh_terms: D015153:Blotting, Western; D039481:CD11b Antigen / Q000378:metabolism*; D018821:CD18 Antigens / Q000378:metabolism*; D002478:Cells, Cultured; D005340:Fibrinogen / Q000378:metabolism*; D006420:Hemeproteins / Q000378:metabolism*; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D016778:Malaria, Falciparum / Q000378:metabolism / Q000469:parasitology; D009000:Monocytes / Q000378:metabolism* / Q000469:parasitology; D010587:Phagocytosis; D010963:Plasmodium falciparum; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
chemical_list: D039481:CD11b Antigen; D018821:CD18 Antigens; D006420:Hemeproteins; C509295:ITGAM protein, human; D016023:Integrins; D017382:Reactive Oxygen Species; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; C020753:hemozoin; D005340:Fibrinogen