Mannose receptor interacts with Fc receptors and is critical for the development of crescentic glomerulonephritis in mice

Chavele, Konstantia-Maria; Martı́nez-Pomares, Luisa; Domin, Jan; Pemberton, Samantha; Haslam, Stuart M.; Dell, Anne; Cook, H. Terence; Pusey, Charles D.; Gordon, Siamon; Salama, Alan D.

doi:10.1172/jci41560

Cited by 57 publications

(44 citation statements)

References 47 publications

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“…ns, not significant. hinge region to FcγR (28,29). For example, signaling events initiated by antigen-bound IgG interacting with Fc-binding molecules on monocytes and macrophages trigger internalization of the FcγR-IgG-antigen complex and FcγR recycling back to the leukocyte surface (30,31).…”

Section: Discussionmentioning

confidence: 99%

Autoantibody-induced internalization of CNS AQP4 water channel and EAAT2 glutamate transporter requires astrocytic Fc receptor

Hinson

Clift

Luo

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Aquaporin-4 (AQP4) water channel-specific IgG distinguishes neuromyelitis optica (NMO) from multiple sclerosis and causes characteristic immunopathology in which central nervous system (CNS) demyelination is secondary. Early events initiating the pathophysiological outcomes of IgG binding to astrocytic AQP4 are poorly understood. CNS lesions reflect events documented in vitro following IgG interaction with AQP4: AQP4 internalization, attenuated glutamate uptake, intramyelinic edema, interleukin-6 release, complement activation, inflammatory cell recruitment, and demyelination. Here, we demonstrate that AQP4 internalization requires AQP4-bound IgG to engage an astrocytic Fcγ receptor (FcγR). IgG-lacking Fc redistributes AQP4 within the plasma membrane and induces interleukin-6 release. However, AQP4 endocytosis requires an activating FcγR's gamma subunit and involves astrocytic membrane loss of an inhibitory FcγR, CD32B. Interaction of the IgG-AQP4 complex with FcγRs triggers coendocytosis of the excitatory amino acid transporter 2 (EAAT2). Requirement of FcγR engagement for internalization of two astrocytic membrane proteins critical to CNS homeostasis identifies a complement-independent, upstream target for potential early therapeutic intervention in NMO.N euromyelitis optica (NMO) is a relapsing inflammatory autoimmune demyelinating disease of the central nervous system (CNS), long considered a severe form of multiple sclerosis (MS). Attacks are generally more severe, onset of paralysis and blindness more rapid (1), and standard MS therapies can worsen NMO (2, 3). A specific serum IgG allows early distinction from MS, thus ensuring timely appropriate therapy (4, 5).The aquaporin-4 (AQP4) water channel is the CNS target (4). Outcomes documented in vitro after NMO-IgG binds to the AQP4 extracellular domain on astrocytes include AQP4 endocytosis and lysosomal degradation, loss of its physically linked major excitatory amino acid transporter 2 (EAAT2), reduced glutamate uptake, impaired water fluxes, granulocyte chemotaxis, and complement factor transcription, secretion, and activation (1, 6-11). Ensuing endothelial permeation of circulating immunoglobulins, complement components, and leukocytes magnifies the initial inflammatory response (6-12). Immunopathological analyses of NMO patients' CNS tissues attest to these events occurring in vivo and inform lesional evolution at the target astrocyte level (1). The blood-brain barrier (BBB) does not absolutely restrict IgG entry into the CNS, but it does exclude macromolecular C1q, essential for activating the classical complement cascade.Experimental studies of lesional events in vitro and in animal models of NMO have emphasized complement-mediated inflammation and astrocyte cytolysis, late events associated with extensive BBB disruption. A neglected potential initiator of NMO pathophysiology is the AQP4-IgG-activated astrocyte's response: synthesis and secretion of complement, cytokines, chemokines (12-14), and inflammatory mediators attracting NMO-characteristic gra...

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Section: Discussionmentioning

confidence: 99%

Autoantibody-induced internalization of CNS AQP4 water channel and EAAT2 glutamate transporter requires astrocytic Fc receptor

Hinson

Clift

Luo

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…30,40,70 In addition, recruited inflammatory monocytes 35,40 that differentiate into inflammatory rMoPh also produce oxygen radicals, hydrogen peroxide, nitric oxide, IL-1, TNF-a, and other effectors of tissue injury. [82][83][84][85][86] The vast majority of reports on this acute phase of injury, whether focused on glomerular or tubulointerstitial compartments, assign responsibility for tissue damage to resident or recruited rMoPh polarized to a classically activated (M1, proinflammatory) Mø phenotype. 27,30 In contrast, later fibrotic phases of injury are orchestrated by resident or recruited rMoPh polarized to an alternatively activated (M2, anti-inflammatory and wound healing) Mø phenotype.…”

Section: Functions Of Rmoph In Immunity Tissue Injury and Tissue Rementioning

confidence: 99%

The Renal Mononuclear Phagocytic System

Nelson

Rees

Griffin

et al. 2012

Journal of the American Society of Nephrology

226

230

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The renal mononuclear phagocytic system, conventionally composed of macrophages (Mø) and dendritic cells (DCs), plays a central role in health and disease of the kidney. Overlapping definitions of renal DCs and Mø, stemming from historically separate research tracks and the lack of experimental tools to specifically study the roles of these cells in vivo, have generated confusion and controversy, however, regarding their immunologic function in the kidney. This brief review provides an appraisal of the current state of knowledge of the renal mononuclear phagocytic system interpreted from the perspective of immunologic function. Physical characteristics, ontogeny, and known functions of the main subsets of renal mononuclear phagocytes as they relate to homeostasis, surveillance against injury and infection, and immune-mediated inflammatory injury and repair within the kidney are described. Gaps and inconsistencies in current knowledge are used to create a roadmap of key questions to be answered in future research.

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“…When human MR cDNA is transfected into Cos cells, these usually non-phagocytic cells express cell surface MR and bind and ingest MR ligands such as zymosan, yeast, and Pneumocystis carinii (Kruskal et al 1992 (Chavele et al 2010) 15.3.5.5 MR Regulates Cell Migration MR has been shown to bind and internalize carbohydrate and collagen ligands and to have a role in myoblast motility and muscle growth. Since the related Endo180 (CD280) receptor has also been shown to have a promigratory role, it was likely that MR may be involved in regulating macrophage migration and/or chemotaxis.…”

Section: Mr As Endocytic Receptor During Entry Ofmentioning

confidence: 99%

Mannose Receptor Family: R-Type Lectins

Gupta

2012

Animal Lectins: Form, Function and Clinical Applications

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Mannose receptor interacts with Fc receptors and is critical for the development of crescentic glomerulonephritis in mice

Cited by 57 publications

References 47 publications

Autoantibody-induced internalization of CNS AQP4 water channel and EAAT2 glutamate transporter requires astrocytic Fc receptor

Autoantibody-induced internalization of CNS AQP4 water channel and EAAT2 glutamate transporter requires astrocytic Fc receptor

The Renal Mononuclear Phagocytic System

Mannose Receptor Family: R-Type Lectins

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