Amelioration of sepsis by inhibiting sialidase-mediated disruption of the CD24-SiglecG interaction

Chen, Guo Yun; Chen, Xi; King, Samantha J.; Cavassani, Karen A.; Cheng, Jiansong; Zheng, Xincheng; Cao, Hongzhi; Yu, Hai; Qu, Jingyao; Fang, Dexing; Wu, Wei; Bai, Xue; Liu, Jin Qing; Woodiga, Shireen A.; Chen, Chong; Sun, Lei; Hogaboam, Cory M.; Kunkel, Steven L.; Zheng, Pan; Liu, Yang

doi:10.1038/nbt.1846

Cited by 170 publications

(202 citation statements)

References 50 publications

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“…However, Siglec-G is expressed both on conventional DCs and on plasmacytoid DCs, as well as on eosinophils. This finding is of importance, as functions for Siglec-G on these DCs were indicated as important for preventing inflammatory responses in a liver damage model as well as for antibacterial responses (9,10). A recent study also showed that Siglec-G was induced in macrophages by RNA viruses and that this Siglec-G upregulation was important for innate immune responses against RNA viruses (19).…”

Section: Discussionmentioning

confidence: 88%

“…A Siglec-G-GFP knockin mouse suggested a broader Siglec-G expression pattern in B cells and several myeloid cell types (8). A functional role of Siglec-G expression on DCs was postulated to be responsible for a Siglec-Gdependent protective effect in a liver injury model and in antibacterial defense (9,10). However, in all of these studies only intracellular expression of Siglec-G was examined because a mAb for determining cell surface expression was not available.…”

Section: The Journal Of Immunologymentioning

confidence: 99%

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The Ligand-Binding Domain of Siglec-G Is Crucial for Its Selective Inhibitory Function on B1 Cells

Hutzler

Özgör

Naito-Matsui

et al. 2014

The Journal of Immunology

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Siglec-G is an inhibitory receptor on B1 cells. Siglec-G–deficient mice show a large B1 cell expansion, owing to higher BCR-induced Ca2+ signaling and enhanced cellular survival. It was unknown why Siglec-G shows a B1 cell–restricted inhibitory function. With a new mAb we could show a comparable Siglec-G expression on B1 cells and conventional B2 cells. However, Siglec-G has a different ligand sialic acid–binding pattern on peritoneal B1 cells than on splenic B cells, and its sialic acid ligands are expressed differentially on these two B cell populations, suggesting that cis-ligand binding plays a crucial role on B1 cells. This observation was further studied by generation of Siglec-G knockin mice with a mutated ligand-binding domain. These mice show increased B1 cell numbers, increased B1 cell Ca2+ signaling, better B1 cell survival, and changes in the B1 cell Ig repertoire. These phenotypes are very similar to Siglec-G–deficient mice. The mutation of the ligand-binding domain of Siglec-G strongly reduces the Siglec-G–IgM association on the B cell surface. Thus, Siglec-G sialic acid–dependent binding to the BCR is crucial for the B1 cell–restricted inhibitory function of Siglec-G and is regulated in an opposite way to that of the related protein CD22 (Siglec-2) on B cells.

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Section: Discussionmentioning

confidence: 88%

Section: The Journal Of Immunologymentioning

confidence: 99%

The Ligand-Binding Domain of Siglec-G Is Crucial for Its Selective Inhibitory Function on B1 Cells

Hutzler

Özgör

Naito-Matsui

et al. 2014

The Journal of Immunology

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“…5 By interacting with Siglec-G/10, an immunoreceptor tyrosine-based inhibition motif (ITIM)-containing negative regulator of inflammation, CD24 has been shown to serve as an essential brake for inflammation induced by damageassociated molecular patterns (DAMPs). 6,7 Bacterial and viral-derived sialidases, which were previously considered virulence factors only in the context of pathogen growth, can disrupt the CD24-Siglec-G/10-mediated negative regulation mechanism by de-sialylation, thereby exacerbating bacteriainduced sepsis. 6 CD24 plays important roles in immune regulation by providing co-stimulatory signals to T cells and B cells.…”

Section: Introductionmentioning

confidence: 99%

“…6,7 Bacterial and viral-derived sialidases, which were previously considered virulence factors only in the context of pathogen growth, can disrupt the CD24-Siglec-G/10-mediated negative regulation mechanism by de-sialylation, thereby exacerbating bacteriainduced sepsis. 6 CD24 plays important roles in immune regulation by providing co-stimulatory signals to T cells and B cells. 5,8 For example, CD24 is critical for T cell homeostasis.…”

Section: Introductionmentioning

confidence: 99%

CD24 blunts oral squamous cancer development and dampens the functional expansion of myeloid-derived suppressor cells

et al. 2016

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CD24 expression has been implicated in the oncogenesis of multiple types of cancer and high tumor expression is considered a poor prognosis factor; however, the role of CD24 in oral cancer progression is unknown. Unlike other cancer types, we found that higher CD24 levels in human oral cancers are correlated to lower clinical stage and better overall survival. We then dissected the role of CD24 and mechanisms in oral cancer pathogenesis in mice using a genetic strategy and demonstrated that CD24 deficiency increased the oral cavity tumor burden in response to the carcinogen 4-nitroquioline 1-oxide (4-NQO). Immune profile analysis showed a significant expansion as well as increased suppressive function of myeloid-derived suppressor cells (MDSCs) in CD24 ¡/¡ mice, but no apparent impairment in T cells, B cells, or dendritic cells. Further, studies with an orthotopically transplanted syngeneic squamous carcinoma model in the tongue of CD24 ¡/¡ and CD24 C/¡ mice confirmed the protective roles of CD24 against cancer. Moreover, the difference in tumor growth between CD24 ¡/¡ and CD24 C/¡ mice was blunted by immunodepletion of MDSCs. We conclude that CD24 expression impedes MDSC expansion and function, and thus slows oral cancer oncogenesis. This study is the first to examine the role of CD24 in a de novo oral cancer model, and it highlights the need to consider the immune regulatory roles of CD24 in the development of CD24-targeted therapy for cancer.

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“…It has been shown that Siglecs play an important role in the internalization of sialic acid-expressing pathogens (17-19), in controlling allergic asthma (20, 21), and in self-tolerance (22). Previously, we found that Siglec G/10-CD24 interaction selectively represses the NF-B-driven inflammatory response to danger-associated molecular patterns (DAMPs), 2 but not pathogen-associated molecular patterns (PAMPs) (23,24 …”

mentioning

confidence: 99%

Induction of Siglec-1 by Endotoxin Tolerance Suppresses the Innate Immune Response by Promoting TGF-β1 Production

Lan

Ren

et al. 2016

Journal of Biological Chemistry

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Sepsis is one of the leading causes of death worldwide. Although the prevailing theory for the sepsis syndrome is a condition of uncontrolled inflammation in response to infection, sepsis is increasingly being recognized as an immunosuppressive state known as endotoxin tolerance. We found sialylation of cell surface was significantly increased on LPS-induced tolerant cells; knockdown of Neu1 in macrophage cell line RAW 264.7 cells resulted in enhanced LPS-induced tolerance, whereas overexpression of Neu1 or treatment with sialidase abrogated LPS-induced tolerance, as defined by measuring TNF-␣ levels in the culture supernatants. We also found that the expression of Siglec-1 (a member of sialic acid-binding Ig (I)-like lectin family members, the predominant sialic acid-binding proteins on cell surface) was specifically up-regulated in endotoxin tolerant cells and the induction of Siglec-1 suppresses the innate immune response by promoting TGF-␤1 production. The enhanced TGF-␤1 production by Siglec-1 was significantly attenuated by spleen tyrosine kinase (Syk) inhibitor. Knockdown of siglec-1 in RAW 264.7 cells resulted in inhibiting the production of TGF-␤1 by ubiquitin-dependent degradation of Syk. Mechanistically, Siglec-1 associates with adaptor protein DNAX-activation protein of 12 kDa (DAP12) and transduces a signal to Syk to control the production of TGF-␤1 in endotoxin tolerance. Thus, Siglec-1 plays an important role in the development of endotoxin tolerance and targeted manipulation of this process could lead to a new therapeutic opportunity for patients with sepsis.Sepsis is generally defined as a systemic inflammatory response syndrome in response to infection. Sepsis can be potentially life threatening; of more than 1 million Americans who are diagnosed with severe sepsis every year, between 28 and 50% will die from this disease (1, 2). It is well-recognized that patients with sepsis are often immune suppressed, a state of reduced responsiveness to endotoxin known as endotoxin tolerance, deaths in this immunosuppressive phase are typically due to failure to control the secondary infections (3-5). The molecular mechanisms underlying this endotoxin tolerance phenomenon is poorly understood.Sialic acids are a family of nine-carbon acidic monosaccharides and are involved in immune response, such as host-pathogen recognition, migration, and antigen presentation. Mounting experimental evidence suggests that the presence of sialic acid residue act as a marker of self in the immune system, as such residues are absent from most microbes (6). Indeed, host cells can be lysed by immune cytotoxic effector mechanisms after extensive desialylation, an observation that demonstrates the significant role played by cell surface sialic acids in the selfrecognition process (7). In addition, normal human serum contains natural antibodies to sialidase-treated red blood cells (7-9), lymphocytes (10), and thymocytes (7). Recently, Meesmann et al. showed that desialylation acted as an "eat me" signal and caused an enhanced upt...

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Amelioration of sepsis by inhibiting sialidase-mediated disruption of the CD24-SiglecG interaction

Cited by 170 publications

References 50 publications

The Ligand-Binding Domain of Siglec-G Is Crucial for Its Selective Inhibitory Function on B1 Cells

The Ligand-Binding Domain of Siglec-G Is Crucial for Its Selective Inhibitory Function on B1 Cells

CD24 blunts oral squamous cancer development and dampens the functional expansion of myeloid-derived suppressor cells

Induction of Siglec-1 by Endotoxin Tolerance Suppresses the Innate Immune Response by Promoting TGF-β1 Production

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