Investigations on the C1q–Calreticulin–Phosphatidylserine Interactions Yield New Insights into Apoptotic Cell Recognition

Païdassi, Helena; Tacnet-Delorme, Pascale; Verneret, Mélanie; Gaboriaud, Christine; Houen, Gunnar; Duus, Karen; Ling, Wai Li; Arlaud, Gérard J.; Frachet, Philippe

doi:10.1016/j.jmb.2011.02.029

Cited by 80 publications

(92 citation statements)

References 55 publications

(83 reference statements)

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“…Remarkably, we observed that the coexternalization of PR3 with CRT occurred only under apoptotic conditions and not during neutrophil degranulation. CRT has been shown to interact directly with PS in other cell types (15). Under apoptotic stress conditions, cytosolic CRT increased and associated with PS, maintaining PS on the cytosolic side of the cell membrane (12).…”

Section: Discussionmentioning

confidence: 99%

“…Accordingly, decreased CRT membrane expression reduced apoptotic cell uptake by phagocytes (12). One of the main receptors of CRT is the low-density lipoprotein receptor-related protein (LRP), also called CD91, found at the surface of phagocytes (13)(14)(15). In this article, we provide evidence that PR3 externalized at the membrane of apoptotic neutrophils can bind and possibly interfere with CRT function, thus impairing phagocytosis of apoptotic neutrophils and promoting inflammation.…”

Section: G Ranulomatosis With Polyangiitis (Gpa) Formerly Calledmentioning

confidence: 97%

“…CRT immobilization running buffer consisted of 10 mM HEPES, 145 mM NaCl, and 5 mM EDTA (pH 7.4). Recombinant CRT, the CRT P domain (residues 189-288), and the CRT globular domain (residues 1-187 fused by a three-residue linker to residues 285-400) were produced as described previously (15) and were diluted in format buffer (pH 3) to 50, 15, and 40 mg/ml, respectively. They were then immobilized on a CM5 sensor chip (GE Healthcare) using the BIAcore amine coupling kit.…”

Section: Surface Plasmon Resonance Spectroscopymentioning

confidence: 99%

“…The specific binding signal shown was obtained by subtracting the background signal, routinely obtained by injection of the sample over an activated-deactivated surface. Data were analyzed by global fitting to a 1:1 Langmuir binding model of the association and dissociation phases for several concentrations of PR3 simultaneously, using the software BIAevaluation, version 3.2 (GE Healthcare), giving a statistic x 2 value ,2, as described previously (15). The apparent equilibrium dissociation constants, K D , were calculated from the ratio of the dissociation and association rate constants,…”

Section: Surface Plasmon Resonance Spectroscopymentioning

confidence: 99%

“…1C). Recombinant CRT, the CRT P domain, and the CRT globular domain designed to preserve the CRT structural domain limits (15,22) were immobilized on a CM5 sensor chip. The kinetic parameters of CRT recognition were determined by recording sensorgrams at varying PR3 concentrations from 10 to 100 nM.…”

Section: Pr3 and Crt Are Colocalized On Neutrophil Membrane On Apoptosismentioning

confidence: 99%

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Proteinase 3, the Autoantigen in Granulomatosis with Polyangiitis, Associates with Calreticulin on Apoptotic Neutrophils, Impairs Macrophage Phagocytosis, and Promotes Inflammation

Gabillet

Millet

Pederzoli-Ribeil

et al. 2012

The Journal of Immunology

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Proteinase 3 (PR3) is the target of anti-neutrophil cytoplasm Abs in granulomatosis with polyangiitis, a form of systemic vasculitis. Upon neutrophil apoptosis, PR3 is coexternalized with phosphatidylserine and impaired macrophage phagocytosis. Calreticulin (CRT), a protein involved in apoptotic cell recognition, was found to be a new PR3 partner coexpressed with PR3 on the neutrophil plasma membrane during apoptosis, but not after degranulation. The association between PR3 and CRT was demonstrated in neutrophils by confocal microscopy and coimmunoprecipitation. Evidence for a direct interaction between PR3 and the globular domain of CRT, but not with its P domain, was provided by surface plasmon resonance spectroscopy. Phagocytosis of apoptotic neutrophils from healthy donors was decreased after blocking lipoprotein receptor-related protein (LRP), a CRT receptor on macrophages. In contrast, neutrophils from patients with granulomatosis with polyangiitis expressing high membrane PR3 levels showed a lower rate of phagocytosis than those from healthy controls not affected by anti-LRP, suggesting that the LRP-CRT pathway was disturbed by PR3-CRT association. Moreover, phagocytosis of apoptotic PR3-expressing cells potentiated proinflammatory cytokine in vitro by human monocyte-derived macrophages and in vivo by resident murine peritoneal macrophages, and diverted the anti-inflammatory response triggered by the phagocytosis of apoptotic cells after LPS challenge in thioglycolate-elicited murine macrophages. Therefore, membrane PR3 expressed on apoptotic neutrophils might amplify inflammation and promote autoimmunity by affecting the anti-inflammatory “reprogramming” of macrophages.

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Section: Discussionmentioning

confidence: 99%

Section: G Ranulomatosis With Polyangiitis (Gpa) Formerly Calledmentioning

confidence: 97%

Section: Surface Plasmon Resonance Spectroscopymentioning

confidence: 99%

Section: Surface Plasmon Resonance Spectroscopymentioning

confidence: 99%

Section: Pr3 and Crt Are Colocalized On Neutrophil Membrane On Apoptosismentioning

confidence: 99%

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Proteinase 3, the Autoantigen in Granulomatosis with Polyangiitis, Associates with Calreticulin on Apoptotic Neutrophils, Impairs Macrophage Phagocytosis, and Promotes Inflammation

Gabillet

Millet

Pederzoli-Ribeil

et al. 2012

The Journal of Immunology

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Apoptotic vesicles restore liver macrophage homeostasis to counteract type 2 diabetes

Zheng

Sui

Zhang

et al. 2021

J of Extracellular Vesicle

116

148

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Apoptosis is a naturally occurring process generating plenty of apoptotic vesicles (apoVs), but the feature, fate and function of apoVs remain largely unknown. Notably, as an appealing source for cell therapy, mesenchymal stem cells (MSCs) undergo necessary apoptosis and release apoVs during therapeutic application. In this study, we characterized and used MSC‐derived apoVs to treat type 2 diabetes (T2D) mice, and we found that apoVs were efferocytosed by macrophages and functionally modulated liver macrophage homeostasis to counteract T2D. We showed that apoVs can induce macrophage reprogramming at the transcription level in an efferocytosis‐dependent manner, leading to inhibition of macrophage accumulation and transformation of macrophages towards an anti‐inflammation phenotype in T2D liver. At the molecular level, we discovered that calreticulin (CRT) was exposed on the surface of apoVs to act as a critical ‘eat‐me’ signal mediating apoV efferocytosis and macrophage regulatory effects. Importantly, we demonstrated that CRT‐mediated efferocytosis of MSC‐derived apoVs contributes to T2D therapy with alleviation of T2D phenotypes including glucose intolerance and insulin resistance. These findings uncover that functional efferocytosis of apoVs restores liver macrophage homeostasis and ameliorates T2D.

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Human red blood cells release microvesicles with distinct sizes and protein composition that alter neutrophil phagocytosis

de Oliveira,

Welsh,

Pinckney

et al. 2023

J of Extracellular Bio

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Extracellular vesicles (EVs) are membrane‐bound structures released by cells and tissues into biofluids, involved in cell‐cell communication. In humans, circulating red blood cells (RBCs), represent the most common cell‐type in the body, generating daily large numbers of microvesicles. In vitro, RBC vesiculation can be mimicked by stimulating RBCs with calcium ionophores, such as ionomycin and A23187. The fate of microvesicles released during in vivo aging of RBCs and their interactions with circulating cells is hitherto unknown. Using SEC plus DEG isolation methods, we have found that human RBCs generate microvesicles with two distinct sizes, densities and protein composition, identified by flow cytometry, and MRPS, and further validated by immune TEM. Furthermore, proteomic analysis revealed that RBC‐derived microvesicles (RBC‐MVs) are enriched in proteins with important functions in ion channel regulation, calcium homeostasis and vesicular transport, such as of sorcin, stomatin, annexin A7 and RAB proteins. Cryo‐electron microscopy identified two separate pathways of RBC‐MV‐neutrophil interaction, direct fusion with the plasma membrane and internalization, respectively. Functionally, RBC‐MVs decrease neutrophil ability to phagocytose Escherichia coli but do not affect their survival at 24 h. This work brings new insights regarding the complexity of the RBC‐MVs biogenesis, as well as their possible role in circulation.

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Investigations on the C1q–Calreticulin–Phosphatidylserine Interactions Yield New Insights into Apoptotic Cell Recognition

Cited by 80 publications

References 55 publications

Proteinase 3, the Autoantigen in Granulomatosis with Polyangiitis, Associates with Calreticulin on Apoptotic Neutrophils, Impairs Macrophage Phagocytosis, and Promotes Inflammation

Proteinase 3, the Autoantigen in Granulomatosis with Polyangiitis, Associates with Calreticulin on Apoptotic Neutrophils, Impairs Macrophage Phagocytosis, and Promotes Inflammation

Apoptotic vesicles restore liver macrophage homeostasis to counteract type 2 diabetes

Human red blood cells release microvesicles with distinct sizes and protein composition that alter neutrophil phagocytosis

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