Identification of human CD93 as the phagocytic C1q receptor (C1qRp) by expression cloning

Schmitz, Peter; Szekeres, Andreas; Wille, Stefan; Stöckl, Johannes; Selenko, Nicole; Prager, Elisabeth; Staffler, Günther; Madic, Otto; Stockinger, Hannes; Knapp, Walter

doi:10.1189/jlb.71.1.133

Cited by 69 publications

(2 citation statements)

References 35 publications

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“…As the initiator in the classical complement cascade, C1q has been found to colocalize with synaptic markers and mediate microglial phagocytosis of synapse (Bialas and Stevens, 2013;Lui et al, 2016;Krukowski et al, 2018). The Type I transmembrane glycoprotein CD93 is a C1q receptor and has also been associated with microglial phagocytosis and inflammation (Nepomuceno and Tenner, 1998;Nepomuceno et al, 1999;Steinberger et al, 2002;Bohlson et al, 2005;Nativel et al, 2019). However, whether CD93 participates in microgliamediated synaptic remodeling remains unknown.…”

Section: Introductionmentioning

confidence: 99%

Microglial Tmem59 Deficiency Impairs Phagocytosis of Synapse and Leads to Autism-Like Behaviors in Mice

et al. 2022

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Synaptic abnormality is an important pathologic feature of autism spectrum disorders (ASDs) and responsible for various behavioral defects in these neurodevelopmental disorders. Microglia are the major immune cells in the brain and also play an important role in synapse refinement. Although dysregulated synaptic pruning by microglia during the brain development has been associated with ASDs, the underlying mechanism has yet to be fully elucidated. Herein, we observed that expression of Transmembrane protein 59 (TMEM59), a protein recently shown to regulate microglial function, was decreased in autistic patients. Furthermore, we found that both male and female mice with either complete or microglia-specific loss of Tmem59 developed ASD-like behaviors. Microglial TMEM59-deficient mice also exhibited enhanced excitatory synaptic transmission, increased dendritic spine density, and elevated levels of excitatory synaptic proteins in synaptosomes. TMEM59-deficient microglia had impaired capacity for synapse engulfment both in vivo and in vitro. Moreover, we demonstrated that TMEM59 interacted with the C1q receptor CD93 and TMEM59 deficiency promoted CD93 protein degradation in microglia. Downregulation of CD93 in microglia also impaired synapse engulfment. These findings identify a crucial role of TMEM59 in modulating microglial function on synapse refinement during brain development and suggest that TMEM59 deficiency may contribute to ASDs through disrupting phagocytosis of excitatory synapse and thus distorting the excitatory-inhibitory (E/I) neuronal activity balance.

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Section: Introductionmentioning

confidence: 99%

Microglial Tmem59 Deficiency Impairs Phagocytosis of Synapse and Leads to Autism-Like Behaviors in Mice

et al. 2022

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“…CD93, corresponding to complement component C1q receptor(C1qRp), acts as a type I transmembrane glycoprotein with a calcium-dependent carbohydrate-binding domain from the C-type superfamily of lectins (Borah et al 2019 ; Steinberger et al 2002 ). It is formed by one single spaning area, one endocellular domain, one C‐type lectin‐like domain, one mucin domain together with five epidermal growth factor (EGF)‐like domains (Greenlee et al 2008 ; McGreal and Gasque 2002 ; Petrenko et al 1999 ).…”

Section: Introductionmentioning

confidence: 99%

CD93 is Associated with Glioma-related Malignant Processes and Immunosuppressive Cell Infiltration as an Inspiring Biomarker of Survivance

Chen

et al. 2022

J Mol Neurosci

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Previous reports have confirmed the significance of CD93 in the progression of multiple tumors; however, there are few studies examining its immune properties for gliomas. Here, we methodically investigated the pathophysiological characteristics and clinical manifestations of gliomas. Six hundred ninety-nine glioma patients in TCGA along with 325 glioma patients in CGGA were correspondingly collected for training and validating. We analyzed and visualized total statistics using RStudio. One-way ANOVA and Student’s t-test were used to assess groups’ differences. All differences were considered statistically significant at the level of P < 0.05. CD93 markedly upregulated among HGG, MGMT promoter unmethylated subforms, IDH wild forms, 1p19q non-codeletion subforms, and mesenchyme type gliomas. ROC analysis illustrated the favorable applicability of CD93 in estimating mesenchyme subform. Kaplan–Meier curves together with multivariable Cox analyses upon survivance identified high-expression CD93 as a distinct prognostic variable for glioma patients. GO analysis of CD93 documented its predominant part in glioma-related immunobiological processes and inflammation responses. We examined the associations of CD93 with immune-related meta-genes, and CD93 positively correlated with HCK, LCK, MHC I, MHC II, STAT1 and IFN, while adverse with IgG. Association analyses between CD93 and gliomas-infiltrating immunocytes indicated that the infiltrating degrees of most immunocytes exhibited positive correlations with CD93, particularly these immunosuppressive subsets such as TAM, Treg, and MDSCs. CD93 is markedly associated with adverse pathology types, unfavorable survival, and immunosuppressive immunocytes infiltration among gliomas, thus identifying CD93 as a practicable marker and a promising target for glioma-based precise diagnosis and therapeutic strategies.

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C1q inhibits immune complex–induced interferon‐α production in plasmacytoid dendritic cells: A novel link between C1q deficiency and systemic lupus erythematosus pathogenesis

Lood¹,

Gullstrand²,

Truedsson³

et al. 2009

Arthritis & Rheumatism

180

132

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Objective. C1q deficiency is the strongest risk factor known for the development of systemic lupus erythematosus (SLE), since almost all humans with a genetic deficiency of C1q develop this disease. Low C1q serum concentration is also a typical finding in SLE during flares, emphasizing the involvement of C1q in SLE pathogenesis. Recent studies have revealed that C1q has a regulatory effect on Toll-like receptorinduced cytokine production. Therefore, we undertook this study to investigate whether C1q could regulate production of interferon-␣ (IFN␣). Methods.Peripheral blood mononuclear cells (PBMCs) and plasmacytoid dendritic cells (PDCs) were stimulated with 3 known interferogenic stimuli and cultured with physiologic concentrations of C1q. IFN␣ production was determined by an immunoassay.Results. C1q significantly inhibited PBMC IFN␣ production induced by RNA-containing immune complexes (ICs), herpes simplex virus (HSV), and CpG DNA. C1q also inhibited PDC IFN␣ production induced by ICs and CpG DNA but increased PDC IFN␣ production induced by HSV. The regulatory role of C1q was not specific for IFN␣ but was also seen for interleukin-6 (IL-6), IL-8, and tumor necrosis factor ␣. We demonstrated binding of C1q to PDCs both by surface plasmon resonance interaction analysis and by flow cytometry, and we also demonstrated intracellular detection of 2 C1q binding proteins.Conclusion. Our findings contribute to the understanding of why C1q deficiency is such a strong risk factor for SLE and suggest an explanation for the up-regulation of the type I IFN system seen in SLE patients.Systemic lupus erythematosus (SLE) is a systemic autoimmune disease involving several organ systems, and it is also characterized by the presence of B cell hyperreactivity, autoantibodies, increased complement consumption, and an ongoing production of type I interferon (IFN) (1). The elevated serum levels of IFN␣ in SLE patients have been proposed to have a significant role in the pathogenesis of SLE. Administration of recombinant IFN␣ to patients with viral infections or malignancies can lead to the development of antinuclear antibodies as well as to SLE or other autoimmune

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Identification of human CD93 as the phagocytic C1q receptor (C1qRp) by expression cloning

Cited by 69 publications

References 35 publications

Microglial Tmem59 Deficiency Impairs Phagocytosis of Synapse and Leads to Autism-Like Behaviors in Mice

Microglial Tmem59 Deficiency Impairs Phagocytosis of Synapse and Leads to Autism-Like Behaviors in Mice

CD93 is Associated with Glioma-related Malignant Processes and Immunosuppressive Cell Infiltration as an Inspiring Biomarker of Survivance

C1q inhibits immune complex–induced interferon‐α production in plasmacytoid dendritic cells: A novel link between C1q deficiency and systemic lupus erythematosus pathogenesis

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