Peptide-Mediated Inhibition of Neutrophil Transmigration by Blocking CD47 Interactions with Signal Regulatory Protein α

Liu, Yuan; O'Connor, Miriam B.; Mandell, Kenneth J.; Zen, Ke; Ullrich, Axel; Bühring, Hans‐Jörg; Parkos, Charles A.

doi:10.4049/jimmunol.172.4.2578

Cited by 58 publications

(57 citation statements)

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“…In support of our observation, a study suggested that a high IL-10 level may be an indicator of disease progression and severity (46). Defective neutrophil migration was observed in the absence of CD47 expression (13). A deficiency or blockade of CD47 is protected from lipopolysaccharide (LPS)-induced acute inflammatory disease and Th2-driven airway inflammation by inhibiting the migration of leukocytes and neutrophils, respectively (44,47).…”

Section: Discussionsupporting

confidence: 74%

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CD47 Plays a Role as a Negative Regulator in Inducing Protective Immune Responses to Vaccination against Influenza Virus

Lee

et al. 2016

J Virol

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An integrin-associated protein CD47, which is a ligand for the inhibitory receptor signal regulatory protein ␣, is expressed on B and T cells, as well as on most innate immune cells. However, the roles of CD47 in the immune responses to viral infection or vaccination remain unknown. We investigated the role of CD47 in inducing humoral immune responses after intranasal infection with virus or immunization with influenza virus-like particles (VLPs). Virus infection or vaccination with VLPs containing hemagglutinin from A/PR8/34 influenza virus induced higher levels of antigen-specific IgG2c isotype dominant antibodies in CD47-deficient (CD47KO) mice than in wild-type (WT) mice. CD47KO mice with vaccination showed greater protective efficacy against lethal challenge, as evidenced by no loss in body weight and reduced lung viral titers compared to WT mice. In addition, inflammatory responses which include cytokine production, leukocyte infiltrates, and gamma interferon-producing CD4 ؉ T cells, as well as an anti-inflammatory cytokine (interleukin-10), were reduced in the lungs of vaccinated CD47KO mice after challenge with influenza virus. Analysis of lymphocytes indicated that GL7 ؉ germinal center B cells were induced at higher levels in the draining lymph nodes of CD47KO mice compared to those in WT mice. Notably, CD47KO mice exhibited significant increases in the numbers of antigen-specific memory B cells in spleens and plasma cells in bone marrow despite their lower levels of background IgG antibodies. These results suggest that CD47 plays a role as a negative regulator in inducing protective immune responses to influenza vaccination. I nfluenza viruses are common pathogens in the respiratory tract that are highly contagious and can cause pulmonary diseases. Seasonal influenza virus variants annually cause significant levels of morbidity and mortality, mostly in infants, the elderly, and sick people (1, 2). Vaccination is the most effective measure to prevent infections with a variety of pathogens, including influenza virus. Virus-like particles (VLPs) are able to effectively stimulate antigen-presenting cells (APCs), which in turn activate T and B cells (3-6). It has been demonstrated that immunization with influenza VLPs can induce protective humoral responses against seasonal and pandemic influenza virus infections (7-9). However, the mechanisms for evoking long-lasting immune responses are largely unknown.CD47 is a transmembrane protein, which is first identified as integrin ␣v␤3. CD47 that is expressed on hematopoietic and nonhematopoietic cells can interact with an inhibitory receptor signal regulatory protein ␣ (SIRP␣) (10). SIRP␣ is also expressed on dendritic cells (DCs) and macrophages, whereas SIRP␣ is barely expressed on B and T cells (11,12). It has been demonstrated that CD47/CD47 and CD47/SIRP␣ interactions are important for DC and neutrophil migration (13,14). In addition, CD11b ϩ DCs in the lungs express both CD47 and SIRP␣, but CD103 ϩ DCs express only CD47. It was also demonstrated t...

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Section: Discussionsupporting

confidence: 74%

“…SIRP␣ is also expressed on dendritic cells (DCs) and macrophages, whereas SIRP␣ is barely expressed on B and T cells (11,12). It has been demonstrated that CD47/CD47 and CD47/SIRP␣ interactions are important for DC and neutrophil migration (13,14). In addition, CD11b ϩ DCs in the lungs express both CD47 and SIRP␣, but CD103 ϩ DCs express only CD47.…”

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CD47 Plays a Role as a Negative Regulator in Inducing Protective Immune Responses to Vaccination against Influenza Virus

Lee

et al. 2016

J Virol

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“…A murine polyclonal antibody specific to SIRP␣ was generated by immunizing mice with a fusion protein consisting of the extracellular domain of human SIRP␣1 (Ig loops 1 ϩ 2 ϩ 3) fused to rabbit Fc (SIRP␣1.ex-Fc) (18). Monoclonal antibodies B4B6 and B1D5 that specifically bind to SIRP␤ were generated as described previously (19).…”

Section: Methodsmentioning

confidence: 99%

SIRPβ1 Is Expressed as a Disulfide-linked Homodimer in Leukocytes and Positively Regulates Neutrophil Transepithelial Migration

Liu

Soto

Qiao

et al. 2005

Journal of Biological Chemistry

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Signal regulatory proteins (SIRPs) comprise a family of cell surface signaling receptors differentially expressed in leukocytes and the central nervous system. Although the extracellular domains of SIRPs are highly similar, classical motifs in the cytoplasmic or transmembrane domains distinguish them as either activating (␤) or inhibitory (␣) isoforms. We reported previously that human neutrophils (polymorphonuclear leukocytes (PMN)) express multiple SIRP isoforms and that SIRP␣ binding to its ligand CD47 regulates PMN transmigration. Here we further characterized the expression of PMN SIRPs, and we reported that the major SIRP␣ and SIRP␤ isoforms expressed in PMN include Bit/PTPNS-1 and SIRP␤1, respectively. Furthermore, although SIRP␣ (Bit/PTPNS-1) is expressed as a monomer, we showed that SIRP␤1 is expressed on the cell surface as a disulfide-linked homodimer with bond formation mediated by Cys-320 in the membrane-proximal Ig loop. Subcellular fractionation studies revealed a major pool of SIRP␤1 within the plasma membrane fractions of PMN. In contrast, the majority of SIRP␣ (Bit/PTPNS-1) is present in fractions enriched in secondary granules and is translocated to the cell surface after chemoattractant (formylmethionylleucylphenylalanine) stimulation. Functional studies revealed that antibody-mediated ligation of SIRP␤1 enhanced formylmethionylleucylphenylalanine-driven PMN transepithelial migration. Co-immunoprecipitation experiments to identify associated adaptor proteins revealed a 10 -12-kDa protein associated with SIRP␤1 that was tyrosine-phosphorylated after PMN stimulation and is not DAP10/12 or Fc receptor ␥ chain. These results provide new insights into the structure and function of SIRPs in leukocytes and their potential role(s) in fine-tuning responses to inflammatory stimuli. Signal regulatory proteins (SIRPs)3 are a family of transmembrane receptor-like signaling proteins that are abundantly expressed in hematopoietic cells, including granulocytes, monocytes, dendritic cells, and lymphocytes (1-3). In addition, SIRPs are expressed in neuronal cells (4 -6) and certain types of cancer cells (7-10). SIRPs can be divided into two subfamilies, SIRP␣ and SIRP␤, based on the putative structures of their C-terminal intracellular domains (11). SIRPs share typical immunoglobulin superfamily structures with an N-terminal extracellular domain containing three cysteine-bound Ig-like loops, a single membrane-spanning transmembrane domain, and a C-terminal intracellular domain (11). The C-terminal intracellular domains of the SIRP␣ subfamily contain a relatively long amino acid sequence (110 amino acids for SIRP␣1) that includes four tyrosine residues to form two immunoreceptor tyrosine-based inhibition motifs (ITIM). Conversely, SIRP␤ subfamily members have a short intracellular domain containing only a few amino acids (4 amino acids for SIRP␤1). Despite a short cytoplasmic tail, SIRP␤1 contains a positively charged lysine in the transmembrane domain that can mediate interactions with an immunoreceptor tyrosi...

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“…As shown in Figure 2A, two CAR-GST recombinants (CAR1 ϩ 2-GST: AA 1-240; CAR1-GST: AA 1-134) and three JAML-Fc recombinants (JAML1-Fc: AA 1-130; JAML2-Fc: AA 141-256; JAML1 ϩ 2-Fc: AA 1-256) were prepared, accordingly. In the experiments, recombinant CD47 and SIRP␣1 extracellular domain fusion proteins CD47-alkaline phosphatase (AP) and SIRP␣-GST were produced as described previously (Seiffert et al, 1999;Liu et al, 2002Liu et al, , 2004a. …”

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Neutrophil Migration across Tight Junctions Is Mediated by Adhesive Interactions between Epithelial Coxsackie and Adenovirus Receptor and a Junctional Adhesion Molecule-like Protein on Neutrophils

Zen

Liu

McCall

et al. 2005

MBoC

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Neutrophil (polymorphonuclear leukocytes [PMN]) transepithelial migration during inflammatory episodes involves INTRODUCTIONPolymorphonuclear leukocytes (PMN) are the first line of host defense against infection by bacterial pathogens and are rapidly recruited to sites of bacterial invasion. Because the majority of pathogens are encountered at mucosal surfaces, PMN must migrate out of the circulation, through the interstitium and across the epithelium to engage offending microbes. Although migration of PMN across the epithelium in this response is a terminal event, it is vitally important since elimination of pathogens and disease pathophysiology are direct consequences of PMN transepithelial migration. Despite the importance of this terminal event in the acute inflammatory response, many of the details regarding the regulation of PMN migration across mucosal surfaces remain undefined. Studies on this have revealed that migration of PMN across epithelial barriers involves a concerted series of cell-cell interactions between the PMN and epithelial cells (Zen and Parkos, 2003;Liu et al., 2004b). There is solid evidence that initial PMN-epithelial binding requires leukocyte ␤ 2 integrins, especially CD11b/CD18 (Parkos, 1997) and that the rate of PMN migration between epithelial cells is dependent on downstream signaling events from binding interactions between epithelial CD47 and PMNexpressed signal regulatory protein ␣ . Recent studies have begun to shed light on the nature of additional receptor-ligand pairs that may regulate PMN transepithelial migration in an organ-specific manner that are distinct from processes regulating transendothelial migration.Although the leukocyte ␤ 2 integrin CD11b/CD18 is a key adhesive element that regulates PMN transepithelial migration, there is evidence that additional adhesion molecules expressed on both PMN and epithelia must participate in PMN transepithelial migration, especially at the level of epithelial intercellular junctions. Recently, certain members of a growing family of proteins termed junctional adhesion molecules (JAMs) that are intercellular junction-associated, type-I Ig superfamily proteins (IgSFs) have been shown to serve as ligands for PMN and monocytes as they migrate across endothelial (Martin-Padura et al., 1998;Del Maschio et al., 1999;Johnson-Leger et al., 2002;Ostermann et al., 2002) and epithelial monolayers (Zen et al., 2004 (Ebnet et al., 2000;Takekuni et al., 2003) or desmosomes (Zen et al., 2004). JAMs are differentially expressed on a variety of endothelia, epithelia, and leukocytes and, under specific conditions, have been shown to mediate homophilic or heterophilic binding interactions that are important in regulating epithelial/endothelial monolayer barrier function and leukocyte transmigration (Martin-Padura et al., 1998;Cunningham et al., 2000;Liu et al., 2000;Cohen et al., 2001;Johnson-Leger et al., 2002;Liang et al., 2002;Mandell et al., 2004). In addition to homophilic/heterophilic interactions among JAM proteins, two family members, JAM-A ...

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Peptide-Mediated Inhibition of Neutrophil Transmigration by Blocking CD47 Interactions with Signal Regulatory Protein α

Cited by 58 publications

References 40 publications

CD47 Plays a Role as a Negative Regulator in Inducing Protective Immune Responses to Vaccination against Influenza Virus

CD47 Plays a Role as a Negative Regulator in Inducing Protective Immune Responses to Vaccination against Influenza Virus

SIRPβ1 Is Expressed as a Disulfide-linked Homodimer in Leukocytes and Positively Regulates Neutrophil Transepithelial Migration

Neutrophil Migration across Tight Junctions Is Mediated by Adhesive Interactions between Epithelial Coxsackie and Adenovirus Receptor and a Junctional Adhesion Molecule-like Protein on Neutrophils

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