CD24 and Siglec-10 Selectively Repress Tissue Damage-Induced Immune Responses

Division of Immunotherapy, Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.
Science (Impact Factor: 33.61). 04/2009; 323(5922):1722-5. DOI: 10.1126/science.1168988
Source: PubMed


Patten recognition receptors, which recognize pathogens or components of injured cells (danger), trigger activation of the
innate immune system. Whether and how the host distinguishes between danger- versus pathogen-associated molecular patterns
remains unresolved. We report that CD24-deficient mice exhibit increased susceptibility to danger- but not pathogen-associated
molecular patterns. CD24 associates with high mobility group box 1, heat shock protein 70, and heat shock protein 90; negatively
regulates their stimulatory activity; and inhibits nuclear factor κB (NF-κB) activation. This occurs at least in part through
CD24 association with Siglec-10 in humans or Siglec-G in mice. Our results reveal that the CD24–Siglec G pathway protects
the host against a lethal response to pathological cell death and discriminates danger- versus pathogen-associated molecular

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Available from: Pan Zheng, May 05, 2015
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    • "Extracellular HMGB1 binds with high affinity to different receptors including the receptor for advanced glycation end products (RAGE), Toll-like receptors (TLRs) 2, 4, and 9, syndecan-1 (CD138), CD24, and Tcell immunoglobulin mucin-3 (Tim-3)[1,2,4]. Notably, CD24[6]and Tim-3[7]are negative regulators of HMGB1 effects on macrophages and tumor-associated dendritic cells (DCs). The signal transduction pathways activated by soluble HMGB1 include NF-í µí¼…B, interferon regulatory factor-3 (IRF- 3), and phosphoinositide-3-kinase (PI3K) and culminate into immune cell activation, induction of proinflammatory cytokines and type I IFN, stimulation of cell proliferation, angiogenesis, cell adhesion and migration, and autophagy[1,2]. "
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    ABSTRACT: High mobility group box 1 (HMGB1) is a member of the “danger associated molecular patterns” (DAMPs) than can localize in various compartments of the cell (from the nucleus to the cell surface) and subserve different functions accordingly. HMGB1 is implicated in maintenance of genomic stability, autophagy, immune regulation, and tumor growth. HMGB1-induced autophagy promotes tumor resistance to chemotherapy, as shown in different models of malignancy, for example, osteosarcoma, leukemia, and gastric cancer. To the best of our knowledge, there is virtually no information on the relationships between HMGB1 and resistance to immunotherapy. A recent study from our group has shed new light on this latter issue. We have demonstrated that targeting of tumor-derived endothelial cells with an anti-human CD31 monoclonal antibody in a human neuroblastoma model was unsuccessful due to a complex chain of events involving the participation of HMGB1. These results are discussed in detail since they provide the first evidence for a role of HMGB1 in resistance of tumor cells to monoclonal antibody-based immunotherapy.
    Full-text · Article · Jan 2016 · Journal of Immunology Research
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    • "Accordingly, here we reasoned that MD-2 may similarly discriminate different HMGB1 isoforms to facilitate TLR4-dependent signaling. of ischemia/reperfusion (I/R; Tsung et al., 2005) or chemical toxicity (Antoine et al., 2013). HMGB1 can signal through a family of receptors, including RAGE (Huttunen et al., 1999), TLR4 (Yang et al., 2010), and cluster of differentiation 24 (CD24)/Siglec-10 (Chen et al., 2009), thereby functioning as a DAMP that alerts, recruits, and activates innate immune cells to produce a wide range of cytokines and chemokines. Thus, seemingly unrelated conditions such as infection and sterile injury can converge on a common process: inflammation , which is orchestrated by HMGB1 actively secreted from innate immune cells or passively released from damaged tissues (Zhang et al., 2010; Andersson and Tracey, 2011). "
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    ABSTRACT: Innate immune receptors for pathogen- and damage-associated molecular patterns (PAMPs and DAMPs) orchestrate inflammatory responses to infection and injury. Secreted by activated immune cells or passively released by damaged cells, HMGB1 is subjected to redox modification that distinctly influences its extracellular functions. Previously, it was unknown how the TLR4 signalosome distinguished between HMGB1 isoforms. Here we demonstrate that the extracellular TLR4 adaptor, myeloid differentiation factor 2 (MD-2), binds specifically to the cytokine-inducing disulfide isoform of HMGB1, to the exclusion of other isoforms. Using MD-2-deficient mice, as well as MD-2 silencing in macrophages, we show a requirement for HMGB1-dependent TLR4 signaling. By screening HMGB1 peptide libraries, we identified a tetramer (FSSE, designated P5779) as a specific MD-2 antagonist preventing MD-2-HMGB1 interaction and TLR4 signaling. P5779 does not interfere with lipopolysaccharide-induced cytokine/chemokine production, thus preserving PAMP-mediated TLR4-MD-2 responses. Furthermore, P5779 can protect mice against hepatic ischemia/reperfusion injury, chemical toxicity, and sepsis. These findings reveal a novel mechanism by which innate systems selectively recognize specific HMGB1 isoforms. The results may direct toward strategies aimed at attenuating DAMP-mediated inflammation while preserving antimicrobial immune responsiveness. © 2015 Yang et al.
    Full-text · Article · Jan 2015 · Journal of Experimental Medicine
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    • "CD24 was then shown to be able to bind HMGB1 and to function as an inhibitor of NF-␬B activation . CD24 though, doesn't have signalling capacities and it has to interact with siglec-10 (siglec-G in mice) as a co-receptor (Chen et al., 2009). CD24 and siglec-10, in turn, seem to have a very specific role in dampening only damage associated inflammation. "
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    ABSTRACT: The ability of the immune system to give rise to an effective response against pathogens while maintaining tolerance towards self-tissues has always been an object of keen interest for immunologist. Over the years, different theories have been proposed to explain if and how the immune system is able to discriminate between self and non-self, including the Infectious Non-self theory from Charles Janeway and Polly Matzinger's Danger theory. Nowadays we know Janeway's theory is largely true, however the immune system does respond to injured, stressed and necrotic cells releasing danger signals (DAMPs) with a potent inflammatory response. To avoid unwanted prolonged autoimmune reactions, though, danger-induced inflammation should be tightly regulated. In the present review we discuss how prototypic DAMPs are able to induce inflammation and the peculiarity of danger-induced inflammation, as opposed to a complete immune response to fight pathogen invasions.
    Full-text · Article · Dec 2014 · Molecular Immunology
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