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Phagocytosis and phagosome maturation are regulated by calcium in J774 macrophages interacting with un-opsonized prey
Linköpings universitet, Institutionen för klinisk och experimentell medicin, Medicinsk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
Linköpings universitet, Institutionen för klinisk och experimentell medicin, Medicinsk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
Linköpings universitet, Institutionen för klinisk och experimentell medicin, Medicinsk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
2002 (engelsk)Inngår i: Bioscience Reports, ISSN 0144-8463, Vol. 22, nr 5-6, s. 529-540Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Phagocytosis by neutrophils, macrophages, and other professional phagocytes requires rapid remodeling of actin. Early phagosomes are surrounded by a rim of F-actin that is disassembled during phagosomoal maturation. Breakdown of periphagosomal F-actin and phagolysosome fusion are calcium dependent processes in neutrophils interacting with serum-opsonized prey, but appears to be calcium independent in macrophages interacting with serum- or IgG-opsonized prey. In the present study, we found that calcium was necessary for phagocytosis, breakdown of periphagosomal F-actin, and phagosomal maturation in J774 macrophages interacting with unopsonized prey. We also observed that lipophosphoglycan (LPG) from Leishmania donovani promastigotes required calcium to exert its inhibitory effect on macrophage phagocytosis and periphagosomal F-actin breakdown. We conclude that calcium is essential for phagocytosis, depolymerization of periphagosomal F-actin, and phagosomal maturation in J774 macrophages interacting with unopsonized prey, as well as for proper functioning of LPG.

sted, utgiver, år, opplag, sider
2002. Vol. 22, nr 5-6, s. 529-540
Emneord [en]
Macrophage, phagocytosis, calcium, actin, phagosome maturation, lipophosphoglycan
HSV kategori
Identifikatorer
URN: urn:nbn:se:liu:diva-13849DOI: 10.1023/A:1022025903688OAI: oai:DiVA.org:liu-13849DiVA, id: diva2:21860
Tilgjengelig fra: 2006-05-23 Laget: 2006-05-23 Sist oppdatert: 2013-09-18
Inngår i avhandling
1. Leishmania donovani Lipophosphoglycan: Modulation of Macrophage and Dendritic Cell Function
Åpne denne publikasjonen i ny fane eller vindu >>Leishmania donovani Lipophosphoglycan: Modulation of Macrophage and Dendritic Cell Function
2006 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
Abstract [en]

Leishmania donovani is a blood-borne tropicial parasite, which infects humans through bites by Phlebotomus sandflies. The parasite survives and multiplies inside macrophages in inner organs, and causes the deadly disease visceral leishmaniasis (Kala-Azar).

Macrophages and dendritic cells (DC) are professional antigen-presenting cells involved in the initiation of immune responses. Immature DC are present in all tissues where they internalise and process antigen, in response to which they migrate from tissue, into draining lymphoid organs, undergo maturation and present antigens to lymphocytes. Control measures for leishmaniasis include testing of new diagnostics and development of affordable and effective vaccines for humans.

Lipophosphoglycan (LPG) is the major surface component of Leishmania donovani promastigotes. LPG comprises a membrane-anchoring lysophosphatidylinositol part and an extracellular chain of disaccharide phosphates. These repetitions are crucial for parasite survival inside macrophages following phagocytosis. LPG has several specific effects on the host cell including inhibition of protein kinase C (PKC) activity, and inhibition of phagosomal maturation, a process requiring depolymerization of periphagosomal F-actin.

Confocal microscopy and image analysis were used to follow F-actin dynamics in single macrophages during phagocytosis of L. donovani promastigotes and LPG-coated particles. F-actin did not depolymerize, but instead progressively polymerized around phagosomes with LPG-containing prey. This correlated with reduced translocation of PKCα to the phagosome and blocked phagosomal maturation. LPG also inhibited cortical actin turnover, which could be the underlying cause of the reduced uptake of LPG-containing prey. Extracellular- and intracellular calcium was necessary for phagocytosis, periphagosomal F-actin breakdown and phagosomal maturation in macrophages interacting with unopsonized prey,and for the action of LPG.

We also studied F-actin turnover in macrophages overexpressing dominant-negative (DN) PKCα. DN PKCα macrophages showed increased amounts of cortical F-actin, decreased phagocytic capacity, inhibition of periphagosomal F-actin breakdown and defective phagosomal maturation. When DN PKCα macrophages interacted with LPG-containing prey, phagocytosis was almost completely blocked.

Moreover, we found that Leishmania promastigotes and particularly LPG inhibit DC maturation and detachment from distinct surfaces. Thus, LPG from Leishmania donovani could directly inhibit DC migration to lymphoid organs, antigen-presentation and development of immunity.

sted, utgiver, år, opplag, sider
Institutionen för molekylär och klinisk medicin, 2006
Serie
Linköping University Medical Dissertations, ISSN 0345-0082 ; 946
Emneord
Lipophosphoglycan, Leishmania donovani, macrophage, actin, phagocytosis, PKC alpha, dendritic cell
HSV kategori
Identifikatorer
urn:nbn:se:liu:diva-6527 (URN)91-85497-84-3 (ISBN)
Disputas
2006-06-01, Linden, Campus US, Linköpings universitet, Linköping, 09:00 (engelsk)
Opponent
Veileder
Tilgjengelig fra: 2006-05-23 Laget: 2006-05-23 Sist oppdatert: 2020-03-29
2. Effects of lipophosphoglycan on macrophage actin dynamics
Åpne denne publikasjonen i ny fane eller vindu >>Effects of lipophosphoglycan on macrophage actin dynamics
2002 (engelsk)Licentiatavhandling, med artikler (Annet vitenskapelig)
Abstract [en]

Leishmania donovani is a blood-borne tropicial parasite, which infects humans through bites by Phlebotomine sandflies. The parasite survives and multiplies inside macrophages in inner organs, and causes the deadly disease visceral leishmaniasis (Kala-Azar). Lipophosphoglycan (LPG) is the major surface component of Leishmania donovani promastigotes. LPG comprises a membrane-anchoring

lysophosphatidylinositol moiety and an extracellular chain of repeating disaccharide phosphates. The repeats are crucial for parasite survival inside macrophages following phagocytosis. LPG has several effects on the host cell including inhibition of protein kinase C (PKC) activity, and inhibition of phagosomal maturation, a process requiring depolymerization of periphagosomal F-actin. Confocal microscopy and image analysis was used to follow F-actin dynamics in single macrophages during phagocytosis of L. donovani promastigotes and LPG-coated particles. F-actin did not depolymerize, but instead progressively polymerized around phagosomes with LPG-containing prey. This directly correlated with reduced translocation of PKCα to the phagosome and blocked phagosomal maturation. It was also found that LPG inhibited cortical actin turnover, which may be the underlying cause of the reduced uptake of LPG-containing prey. Free calcium was necessary for phagocytosis, periphagosomal F-actin breakdown and phagosomal maturation in macrophages interacting with unopsonized prey. LPG required free calcium to exert its inhibitory effects on these processes. We also studied F -actin turnover in macrophages overexpressing dominant-negative (DN) PKCα. DN PKCα macrophages showed increased amounts of cortical F-actin, decreased phagocytic capacity, inhibition of periphagosomal F-actin breakdown and defective phagosomal maturation. When DN PKCa macrophages interacted with LPG-containing prey, phagocytosis was almost completely blocked.

Together, our results indicate that blockage of F-actin breakdown through inhibition of PKCa by LPG reduces phagocytosis and is instrumental for the inhibition of phagosomal maturation induced by L. donovani promastigotes.

sted, utgiver, år, opplag, sider
Linköping: Linköpings universitet, 2002. s. 42
Serie
Linköping Studies in Health Sciences. Thesis, ISSN 1100-6013 ; 58
HSV kategori
Identifikatorer
urn:nbn:se:liu:diva-26683 (URN)11250 (Lokal ID)91-7373-190-0 (ISBN)11250 (Arkivnummer)11250 (OAI)
Presentation
2002-12-10, Hälsouniversitetet, Linköping, 10:15 (svensk)
Tilgjengelig fra: 2009-10-08 Laget: 2009-10-08 Sist oppdatert: 2013-09-18

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