The class I scavenger receptor CD163 promotes internalization of ADAMTS13 by macrophages

Verbij, Fabian C.; Sorvillo, Nicoletta; Kaijen, Paul; Hrdinová, Johana; Peyron, Ivan; Fijnheer, Rob; Brinke, Anja ten; Meijer, Alexander B.; Alphen, Floris P.J. van; Berg, Timo K. van den; Graversen, Jonas Heilskov; Moestrup, Søren K.; Voorberg, Jan

doi:10.1182/bloodadvances.2016001321

Cited by 11 publications

(11 citation statements)

References 54 publications

(70 reference statements)

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“… 37 More recently, we described the involvement of CD163 in the internalization of ADAMTS13 by macrophages in vitro . 38 In the latter study, we observed that the uptake efficiency of CD163-positive macrophages was approximately 10 times higher when compared to that of mo-DCs (that are devoid of CD163 expression). Based on this finding, it is tempting to speculate that the limited presentation of ADAMTS13-derived peptides on mo-DCs is due to a relatively low efficiency to internalize ADAMTS13, thereby limiting the number of ADAMTS13-derived peptides that are presented.…”

Section: Discussionmentioning

confidence: 66%

Mass spectrometry-assisted identification of ADAMTS13-derived peptides presented on HLA-DR and HLA-DQ

et al. 2018

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Formation of microthrombi is a hallmark of acquired thrombotic thrombocytopenic purpura. These microthrombi originate from insufficient processing of ultra large von Willebrand factor multimers by ADAMTS13 due to the development of anti-ADAMTS13 autoantibodies. Several studies have identified the major histocompatibility complex class II alleles HLA-DRB1*11, HLA-DQB1*03 and HLA-DQB1*02:02 as risk factors for acquired thrombotic thrombocytopenic purpura development. Previous research in our department indicated that ADAMTS13 CUB2 domain-derived peptides FINVAPHAR and LIRDTHSLR are presented on HLA-DRB1*11 and HLA-DRB1*03, respectively. Here, we describe the repertoire of ADAMTS13 peptides presented on HLA-DQ. In parallel, the repertoire of ADAMTS13-derived peptides presented on HLA-DR was monitored. Using HLA-DR- and HLA-DQ-specific antibodies, we purified HLA/peptide complexes from ADAMTS13-pulsed monocyte-derived dendritic cells. Using this approach, we identified ADAMTS13-derived peptides presented on HLA-DR for all 9 samples analyzed; ADAMTS13-derived peptides presented on HLA-DQ were identified in 4 out of 9 samples. We were able to confirm the presentation of the CUB2 domain-derived peptides FINVAPHAR and LIRDTHSLR on HLA-DR. In total, 12 different core-peptide sequences were identified on HLA-DR and 8 on HLA-DQ. For HLA-DR11, several potential new core-peptides were found; 4 novel core-peptides were exclusively identified on HLA-DQ. Furthermore, an in silico analysis was performed using the EpiMatrix and JanusMatrix tools to evaluate the eluted peptides, in the context of HLA-DR, for putative effector or regulatory T-cell responses at the population level. The results from this study provide a basis for the identification of immuno-dominant epitopes on ADAMTS13 involved in the onset of acquired thrombotic thrombocytopenic purpura.

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Section: Discussionmentioning

confidence: 66%

Mass spectrometry-assisted identification of ADAMTS13-derived peptides presented on HLA-DR and HLA-DQ

et al. 2018

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“…sCD163 function is unclear, but it was shown to potentiate IL‐10 expression in allergen‐activated PBMCs 65 and to inhibit T cell activation/proliferation, 66 hence promoting inflammatory resolution. CD163 facilitates the hemoglobin‐haptoglobin complex 67 and ADAMTS13 68 internalization. Our analysis showed no direct binding between CD163 and α‐syn, regardless of calcium concentration, suggesting that α‐syn is not a direct ligand for CD163 (possible coreceptor interactions cannot be excluded).…”

Section: Discussionmentioning

confidence: 99%

Soluble CD163 Changes Indicate Monocyte Association With Cognitive Deficits in Parkinson's Disease

et al. 2020

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A BS TRACT: Background: Parkinson's disease (PD) is a neurodegenerative disorder with a significant immune component, as demonstrated by changes in immune biomarkers in patients' biofluids. However, which specific cells are responsible for those changes is unclear because most immune biomarkers can be produced by various cell types. Objectives: The aim of this study was to explore monocyte involvement in PD. Methods: We investigated the monocyte-specific biomarker sCD163, the soluble form of the receptor CD163, in cerebrospinal fluid (CSF) and serum in two experiments, and compared it with other biomarkers and clinical data. Potential connections between CD163 and alpha-synuclein were studied in vitro. Results: CSF-sCD163 increased in late-stage PD and correlated with the PD biomarkers alpha-synuclein, Tau, and phosphorylated Tau, whereas it inversely correlated with the patients' cognitive scores, supporting monocyte involvement in neurodegeneration and cognition in PD. Serum-sCD163 increased only in female patients, suggesting a sex-distinctive monocyte response. CSF-sCD163 also correlated with molecules associated with adaptive and innate immune system activation and with immune cell recruitment to the brain. Serum-sCD163 correlated with proinflammatory cytokines and acute-phase proteins, suggesting a relation to chronic systemic inflammation. Our in vitro study showed that alpha-synuclein activates macrophages and induces shedding of sCD163, which in turn enhances alpha-synuclein uptake by myeloid cells, potentially participating in its clearance. Conclusions: Our data present sCD163 as a potential cognition-related biomarker in PD and suggest a role for monocytes in both peripheral and brain immune responses. This may be directly related to alpha-synuclein's proinflammatory capacity but could also have consequences for alpha-synuclein processing.

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“…In addition, sCD163 seems to inhibit T cell activation and proliferation [58]. It is known that CD163 is in charge of the uptake of the hemoglobin-haptoglobin complex [40] and ADAMTS13 [83]. In order to assess whether α-syn could be a cognate for CD163, we did MST to assess co-interaction.…”

Section: Discussionmentioning

confidence: 99%

“…sCD163 function is unclear, but it was shown to potentiate IL-10 expression in allergen-activated PBMCs 65 and to inhibit T cell activation/proliferation 66 , hence promoting inflammatory resolution. CD163 facilitates hemoglobin-haptoglobin complex 67 and ADAMTS13 68 internalization. Our analysis showed no direct binding between CD163 and α-syn, regardless of calcium concentration, suggesting that α-syn is not a direct ligand for CD163 (possible co-receptor interactions cannot be excluded).…”

Section: Discussionmentioning

confidence: 99%

“Changes in soluble CD163 indicate monocyte involvement in cognitive deficits in Parkinson’s disease”

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et al. 2020

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Parkinson's disease is a neurodegenerative disorder with a significant immune component. Numerous studies have reported alterations on immune biomarkers in CSF and serum that associate with symptoms in PD patients. However, it is unclear, which specific immune cells are responsible for the changes in those biomarkers; since most of these cytokines or chemokines, can be produced by a variety of immune cells, or even neurons or glia cells in the brain. Here, we investigate a monocyte/macrophage-specific biomarker: sCD163, the soluble form of the receptor CD163. Our data from tow cohorts show that the CSF-sCD163 increases as the disease progresses, together with a correlated increase in PD-specific as well as neurodegeneration-associated disease biomarkers: alpha-synuclein, tau, and phosphorylated-Tau. Moreover, CSF-sCD163 levels were inversely correlated to the cognitive scores MMSE and MOCA, with higher sCD163 indicating lower cognitive capacity. sCD163 was also increased in serum, although only in female PD patients, suggesting a gender distinctive monocyte-related immune response. CSF-sCD163 also correlated with molecules associated with endothelial cells, tissue infiltration, and activation of B cells and T cells in the PD patients. This suggests activation of both the adaptive and the innate immune system along with recruitment of lymphocytes and monocytes to sites of inflammation in the brain. In serum, sCD163 was associated with pro-inflammatory cytokines and acute phase proteins, suggesting a relation to chronic systemic inflammation. Interestingly, our in vitro study suggests that sCD163 might enhance alpha-synuclein uptake by myeloid cells without direct binding, thus participating in the clearance of alpha-synuclein. Accordingly, our data supports sCD163 as a potential cognition-related biomarker in PD and corroborates a role for monocytes both in peripheral and brain immune responses that could have direct consequences in the handling of alpha-synuclein

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The class I scavenger receptor CD163 promotes internalization of ADAMTS13 by macrophages

Cited by 11 publications

References 54 publications

Mass spectrometry-assisted identification of ADAMTS13-derived peptides presented on HLA-DR and HLA-DQ

Mass spectrometry-assisted identification of ADAMTS13-derived peptides presented on HLA-DR and HLA-DQ

Soluble CD163 Changes Indicate Monocyte Association With Cognitive Deficits in Parkinson's Disease

“Changes in soluble CD163 indicate monocyte involvement in cognitive deficits in Parkinson’s disease”

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