Receptor-mediated endocytosis of immune complexes in rat liver sinusoidal endothelial cells is mediated by FcγRIIb2

Mousavi, Seyed Ali; Sporstøl, Marita; Fladeby, Cathrine; Kjeken, Rune; Barois, Nicolas; Berg, Trond

doi:10.1002/hep.21748

Cited by 97 publications

(128 citation statements)

References 61 publications

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“…In addition, however, Fc␥RIIB in mouse dendritic cells can recycle bound immune complexes to the cell surface and prevent their delivery to degradative compartments that is required for antigen processing (30,31). Recycling of a portion of internalized immune complexes to the cell surface was also observed with rat Fc␥RIIB in liver sinusoidal endothelial cells (33). Such routing of immune complexes away from a degradative fate will depend on the persistence of their binding to receptors.…”

Section: Discussionmentioning

confidence: 99%

Divergent Intracellular Sorting of FcγRIIA and FcγRIIB2*

Zhang

Booth

2010

Journal of Biological Chemistry

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The human low affinity Fc␥RII family includes both the activating receptor Fc␥RIIA and the inhibitory receptor Fc␥RIIB2. These receptors have opposing signaling functions but are both capable of internalizing IgG-containing immune complexes through clathrin-mediated endocytosis. We demonstrate that upon engagement by multivalent aggregated human IgG, Fc␥RIIA expressed in ts20 Chinese hamster fibroblasts is delivered along with its ligand to lysosomal compartments for degradation, while Fc␥RIIB2 dissociates from the ligand and is routed separately into the recycling pathway. Fc␥RIIA sorting to lysosomes requires receptor multimerization, but does not require either Src family kinase activity or ubiquitylation of receptor lysine residues. The sorting of Fc␥RIIB2 away from a degradative fate is not due to its lower affinity for IgG and occurs even upon persistent receptor aggregation. Upon co-engagement of Fc␥RIIA and Fc␥RIIB2, the receptors are sorted independently to distinct final fates after dissociation of co-clustering ligand. These results reveal fundamental differences in the trafficking behavior of different Fc␥ receptors.Fc␥ receptors (Fc␥R) 2 are key players in immune responses. Widely expressed on cells of the hematopoietic system, these receptors mediate a multitude of biological responses that are triggered upon receptor engagement by multivalent IgG-containing immune complexes (1). These responses include production of inflammatory cytokines, antibody-dependent cellular cytotoxicity, and induction of dendritic cell maturation. Fc␥R also mediate the internalization of immune complexes. Soluble immune complexes are internalized by clathrin-mediated endocytosis whereas large (Ͼ0.5 m) antibody-coated particles are internalized via phagocytosis. These uptake processes are important in host defense against infection; moreover, defects in immune complex clearance are associated with the development of autoimmunity (2).Fc␥Rs can be categorized into two functional groups. The activating Fc␥R have an immunoreceptor tyrosine-based activation motif (ITAM) within the cytoplasmic domain of the receptor itself or an associated FcR␥ signaling subunit. Phosphorylation of tyrosine residues in the ITAM by Src family kinases after receptor aggregation initiates signaling cascades that trigger downstream effector responses (3). In contrast, inhibitory Fc␥R contain an immunoreceptor tyrosine-based inhibitory motif (ITIM), which recruits phosphatases that antagonize ITAM-mediated signaling. Therefore, the responsiveness of effector cells to immune complexes is determined by the balance between activating and inhibitory receptors (1).A feature of the human immune system that distinguishes it from that of mouse is the presence of both activating and inhibitory members of the low affinity Fc␥RII subfamily. Fc␥RIIA is an activating Fc␥R unique to humans and other primates, and is the most widely expressed Fc␥R on human leukocytes (4). In addition, Fc␥RIIA is unusual among activating Fc␥R in having both ligand binding and ITA...

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Section: Discussionmentioning

confidence: 99%

Divergent Intracellular Sorting of FcγRIIA and FcγRIIB2*

Zhang

Booth

2010

Journal of Biological Chemistry

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“…17, [46][47][48][49] An important question must focus on the conditions that favor killing of targeted cells (the preferred outcome) vs escape via trogocytosis. In almost all of these treated CLL patients, complement titers in the bloodstream were reduced considerably after CD20 mAb infusions, indicating this effector function was exhausted.…”

Section: Modern Times and Mechanismsmentioning

confidence: 99%

“…[70][71][72] The internalization of Mylotarg by CD33 1 cells is relatively slow (takes many hours), and this could allow enough time for circulating Mylotarg-opsonized cells to transfer their deadly cargo to LSECs via trogocytosis when they circulate through the liver. FcgRIIb on LSECs can clear circulating immune complexes, 46,47,49 and acceptor cell-associated FcgRIIb can promote trogocytosis and remove RTX (human IgG1)-CD20 complexes from opsonized B cells. 22 The affinity of FcgRIIb for IgG4 is modestly lower than for human IgG1, 73 but it is quite reasonable to expect that aggregated Mylotarg complexes bound to circulating CD33 1 cells could reach the multivalent avidity threshold necessary for chelation by a cluster of FcgRIIb on the LSEC, thereby allowing trogocytosis.…”

mentioning

confidence: 99%

Fcγ-receptor–mediated trogocytosis impacts mAb-based therapies: historical precedence and recent developments

Taylor

Lindorfer

2015

Blood

132

118

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A specialized form of trogocytosis occurs when Fcg receptors on acceptor cells take up and internalize donor cell-associated immune complexes composed of specific monoclonal antibodies (mAbs) bound to target antigens on donor cells. This trogocytosis reaction, an example of antigenic modulation, has been described in recent clinical correlative studies and in vitro investigations for several mAbs used in cancer immunotherapy, including rituximab and ofatumumab. We discuss the impact of Fcg-receptor-mediated trogocytosis on the efficacy of cancer immunotherapy and other mAb-based therapies. (Blood. 2015;125(5):762-766)

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“…To fulfill their clearance functions, LSECs express 3 major types of scavenger receptors: (a) the macrophage mannose receptor binding denatured collagen (3) and collagen peptides preventing gelatin formation in the circulation, tissue plasminogen activator regulating fibrinolytic activity, and lysosomal enzymes that are recruited for further use in LSEC (4); (b) the Fcγ receptors FcγRII in the human system (5) and FcγRIIB2 in the rat (6,7); and (c) the major LSEC hyaluronan (HA) scavenger receptor. Upon identification and cloning of the stabilin family of fasciclin-like HA receptor homologs by our group (8), the identity of the LSEC HA scavenger receptor was established as stabilin-2 on the basis of HA affinity purification and sequencing (9).…”

Section: Introductionmentioning

confidence: 99%

Deficiency of liver sinusoidal scavenger receptors stabilin-1 and -2 in mice causes glomerulofibrotic nephropathy via impaired hepatic clearance of noxious blood factors

Schledzewski¹,

Géraud²,

Arnold³

et al. 2011

J. Clin. Invest.

140

158

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Tissue homeostasis and remodeling are processes that involve high turnover of biological macromolecules. Many of the waste molecules that are by-products or degradation intermediates of biological macromolecule turnover enter the circulation and are subsequently cleared by liver sinusoidal endothelial cells (LSEC). Besides the mannose receptor, stabilin-1 and stabilin-2 are the major scavenger receptors expressed by LSEC. To more clearly elucidate the functions of stabilin-1 and -2, we have generated mice lacking stabilin-1, stabilin-2, or both stabilin-1 and -2 (Stab1 -/-Stab2 -/-mice). Mice lacking either stabilin-1 or stabilin-2 were phenotypically normal; however, Stab1 -/-Stab2 -/-mice exhibited premature mortality and developed severe glomerular fibrosis, while the liver showed only mild perisinusoidal fibrosis without dysfunction. Upon kidney transplantation into WT mice, progression of glomerular fibrosis was halted, indicating the presence of profibrotic factors in the circulation of Stab1 -/-Stab2 -/-mice. While plasma levels of known profibrotic cytokines were unaltered, clearance of the TGF-β family member growth differentiation factor 15 (GDF-15) was markedly impaired in Stab1 -/-Stab2 -/-mice but not in either Stab1 -/-or Stab2 -/-mice, indicating that it is a common ligand of both stabilin-1 and stabilin-2. These data lead us to conclude that stabilin-1 and -2 together guarantee proper hepatic clearance of potentially noxious agents in the blood and maintain tissue homeostasis not only in the liver but also distant organs.

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Receptor-mediated endocytosis of immune complexes in rat liver sinusoidal endothelial cells is mediated by FcγRIIb2

Cited by 97 publications

References 61 publications

Divergent Intracellular Sorting of FcγRIIA and FcγRIIB2*

Divergent Intracellular Sorting of FcγRIIA and FcγRIIB2*

Fcγ-receptor–mediated trogocytosis impacts mAb-based therapies: historical precedence and recent developments

Deficiency of liver sinusoidal scavenger receptors stabilin-1 and -2 in mice causes glomerulofibrotic nephropathy via impaired hepatic clearance of noxious blood factors

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