CD22 modulation regulates neuroinflammation in microglia
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus Homo sapiens
PROVIDER: GSE269121 | GEO | 2024/06/10
REPOSITORIES: GEO
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Project description:CD22 modulation regulates neuroinflammation in microglia
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Project description:CD22 (Siglec-2) is a member of the Siglec family. It is an inhibitory co-receptor of the B-cell-receptor (BCR) and inhibits B–cell activation. Upon BCR stimulation ITIMs in the cytoplasmic tail of CD22 are phosphorylated. This triggers CD22 signalling pathways, which lead to a decreased calcium mobilization in the B cell and thus an inhibition of BCR signalling. Although some CD22 binding partners, such as the phosphatase SHP-1, have already been identified, we deciphered the CD22 interactome in more detail, to gain a deeper understanding of CD22 molecular mechanisms and signalling events after BCR activation. Stable isotope labelling of amino acids in cell culture (SILAC) in combination with mass spectrometry analysis enabled the identification of specific CD22 interaction partners in a quantitative proteomics approach. Hereby, several new CD22 associated proteins were identified that have not been linked to CD22 yet. One of those interacting proteins is cullin 3, an E3 ubiquitin ligase. It was revealed that cullin 3 is important for clathrin-dependent CD22 internalization after BCR stimulation and CD22 surface expression. Further analysis of B-cell specific cullin 3 deficient mice showed an important role of cullin 3 in B cell development. These mice have strongly reduced numbers of mature B cells in the periphery, which are characterized by increased CD22 expression and additionally by pre-activated and apoptotic phenotypes.
2020-05-06 | PXD013801 | Pride
Project description:We report that antibody-mediated CD22 blockage leads to an altered transcriptomic signature profile which, by further evaluating the affected genes, resembles a homeostatic phenotype.
2021-03-30 | GSE169252 | GEO
Project description:Neuroinflammation is a crucial driver of multiple neurodegenerative diseases, including Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD). Yet, therapeutic targets for neurodegenerative diseases based on neuroinflammation still warrant investigation. CD22 has been implicated in neuroinflammatory diseases, namely AD. Specifically, plasma soluble CD22 (sCD22) level is upregulated in patients with AD. Direct experimental evidence for the role of CD22 in neuroinflammation is needed, as is a better understanding of its impact on microglia activation and therapeutic potential. Here we reported that sCD22 promotes neuroinflammation both in vivo and in vitro. sCD22 activated microglia via both p38 and ERK1/2 signaling pathway for the secretion of TNFα, IL-6 and CCL3. Moreover, sCD22 activated microglia via sialic acid binding domain and 2,6 linked sialic acid glycan on sCD22. The pivotal therapeutic potential of targeting CD22 was demonstrated in Amyloid β (Aβ) induced-neuroinflammation in hCD22 transgenic mice. Suciraslimab improved working memory and resolved neuroinflammation in vivo. Further, membrane CD22 inhibited Amyloid β (Aβ) induced-NFκB signaling pathway and mechanistic study delineated that suciraslimab suppressed Aβ-induced IL-1β secretion in human microglia and PBMC. Suciraslimab also suppressed IL-12 and IL-23 secretion in human PBMC. Moreover, suciraslimab reduced the surface expression of α4 integrin on B cells. Intriguingly, we discovered that CD22 interact with Aβ and suciraslimab enhanced internalization of CD22-Aβ complex in microglia. Our data highlights the importance of sCD22 in driving neuroinflammation and the dual mechanism of targeting CD22 to resolve Aβ-induced inflammation and promote Aβ phagocytosis.
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Project description:Sequencing data related to the manuscript entitled, "CD22 blockade restores homeostatic microglial phagocytosis in the aging brain."
2019-03-01 | GSE127543 | GEO
Project description:Chimeric antigen receptor (CAR) T cells are effective against B-cell malignancies but are associated with cytokine-driven inflammatory toxicities such as cytokine release syndrome (CRS). Historically, T cell receptor (TCR) engineered T cell therapies are rarely associated with CRS. However, it is challenging to compare diverse cell products utilized in different clinical contexts and against different antigens. In this study, TCR and CAR were made to target the same source of antigen, CD22, expressed by B-cell malignancies: the TCR recognizes CD22-derived peptide processed and presented in the context of HLA-A*02:01, and the CAR recognizes CD22 protein expressed on the cell surface. In vivo studies comparing the CD22 TCR-T cells to CD22 CAR-T cells demonstrated that the TCR-T cells could clear leukemia without inducing systemic proinflammatory cytokine elevation, whereas CD22 CAR-T cells induced high levels of circulating proinflammatory cytokine reminiscent of CRS. T cells activated through either the TCR or CAR by an identical leukemia cell line demonstrated differential transcriptional responses. T cells activated via the CAR had disproportionate and significant upregulation of inflammatory gene sets compared to T-cells activated via the TCR.
2025-04-16 | GSE255323 | GEO
Project description:CD22 (also known as Siglec-2) belongs to the Siglec family of glycan-recognition proteins and negatively regulates B-cell receptor-mediated signaling. CD22 protein is known to be down-regulated in the B cells of patients with chronic lymphocytic leukemia (CLL). However, the mechanism regulating the transcription of CD22 is incompletely understood. In this study, we defined the minimal promoter region of the human CD22 gene, and systematically identified the proteins binding to the minimal promoter by DNA affinity-purification from the nuclear extracts of B cell lines and LC-MS/MS.
2025-03-26 | PXD054553 | Pride
Project description:Sphingomonas sp. CD22 Genome sequencing and assembly
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Project description:Clostridioides difficile CD22 Genome sequencing and assembly
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Project description:Chimeric antigen receptor (CAR) T cells targeting CD19 are highly effective against B-lineage malignancies. However, about half of patients either fail to achieve complete remission (in the case of lymphoma) or relapse (in the case of acute lymphoblastic leukemia). CD22 represents an alternative highly B-lineage-restricted target. Although CD22-targeted CAR T cells are clinically active, targeting this antigen has proven difficult relative to CD19, attributable, in part, to lower expression levels. Commonly, patients relapse or progress with reduced CD22 expression compared to pre-treatment, contrasting with the loss of CD19 expression typically observed after CD19-CAR therapy. Prior work demonstrated that an antigen-independent “tonic” signaling CD22-CAR has enhanced clinical efficacy relative to other CD22-CARs tested. However, tonic signaling has been shown to be detrimental to long-term CAR T cell function. Here, we demonstrate a balance between binding affinity and antigen-independent signaling (determined by length of the linker between fragment variable regions) in determining CAR function against CD22. We show that CAR function against both CD22Lo and WT leukemia can be augmented by boosting binding affinity without shortening the linker to induce tonic signaling, establishing rational combinatorial modification of antigen binding domain as an important approach for modulating the function of cellular therapeutics.
2025-12-17 | GSE313971 | GEO