Targeting SIRP‐α protects from type 2‐driven allergic airway inflammation

Raymond, Marianne; Van, Vu Quang; Rubio, Manuel; Welzenbach, Karl; Sarfati, Marika

doi:10.1002/eji.201040797

Cited by 20 publications

(20 citation statements)

References 36 publications

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“…In addition, it was reported that macrophages showed increased phagocytosis of cancer cells in the absence of CD47-mediated signaling (43). Interestingly, SIRP␣-Fc treatment interfering with the CD47 pathway was able to reduce Th2-driven allergic airway inflammation (44), a finding which is in line with the results of IgG2c dominant antibody responses in CD47KO mice after i.n. VLP vaccination.…”

Section: Discussionsupporting

confidence: 73%

“…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). However, in the present study, naive CD47KO mice showed higher or similar cellularity of neutrophils in the BALF and lungs compared to those in naive WT mice upon influenza virus infection, suggesting no defect in the migration of CD47-deficient neutrophils into the lungs.…”

Section: Discussionmentioning

confidence: 99%

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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: 73%

Section: Discussionmentioning

confidence: 99%

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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“…SIRP␣ proteolysis may modify numerous diseases where SIRP␣ signaling has been implicated including cancer (26), renal ischemia reperfusion injury (27), stroke (28), Crohn disease, (29), and allergic airway inflammation (30).…”

Section: Discussionmentioning

confidence: 99%

Cleavage of Signal Regulatory Protein α (SIRPα) Enhances Inflammatory Signaling

Londino

Gulick

Isenberg

et al. 2015

Journal of Biological Chemistry

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Signal regulatory protein ␣ (SIRP␣) is a membrane glycoprotein immunoreceptor abundant in cells of monocyte lineage. SIRP␣ ligation by a broadly expressed transmembrane protein, CD47, results in phosphorylation of the cytoplasmic immunoreceptor tyrosine-based inhibitory motifs, resulting in the inhibition of NF-B signaling in macrophages. Here we observed that proteolysis of SIRP␣ during inflammation is regulated by a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10), resulting in the generation of a membrane-associated cleavage fragment in both THP-1 monocytes and human lung epithelia. We mapped a charge-dependent putative cleavage site near the membrane-proximal domain necessary for ADAM10-mediated cleavage. In addition, a secondary proteolytic cleavage within the membrane-associated SIRP␣ fragment by ␥-secretase was identified. Ectopic expression of a SIRP␣ mutant plasmid encoding a proteolytically resistant form in HeLa cells inhibited activation of the NF-B pathway and suppressed STAT1 phosphorylation in response to TNF␣ to a greater extent than expression of wild-type SIRP␣. Conversely, overexpression of plasmids encoding the proteolytically cleaved SIRP␣ fragments in cells resulted in enhanced STAT-1 and NF-B pathway activation. Thus, the data suggest that combinatorial actions of ADAM10 and ␥-secretase on SIRP␣ cleavage promote inflammatory signaling.Inhibitory receptors including signal regulatory protein ␣ (SIRP␣), 2 CD33, SIGLECs (sialic acid-binding immunoglobulin-type lectins), CD66a, PD-1, CD31, PILRa (paired immunoglobin-like type 2 receptor ␣), CMRF35H, gp49B1, PECAM1, and others have been demonstrated to suppress the initiation of inflammatory signaling and contribute to the resolution of inflammation after infection (1, 2). SIRP␣ is membrane glycoprotein immunoreceptor that is expressed mainly in myeloid and neuronal cells (3). Ligation of SIRP␣ results in phosphorylation of the cytoplasmic immunoreceptor tyrosine-based inhibitory motifs (ITIMs), which recruit and activate SH2 domain-containing phosphotyrosine phosphatases SHP-1 and SHP-2 (4). SIRP␣ signaling results in reduced macrophage migration and phagocytosis and inhibition of NF-B signaling with reduction of release of NF-B-dependent cytokines in macrophages (5, 6). Phosphorylation of SIRP␣ ITIM domains also enhances JAK/STAT activation and NADPH oxidase expression and activity (7). Thus, SIRP␣ serves as an important modulator of the host adaptive immune response. Proteolysis and release of the SIRP␣ NH 2 -terminal domain has been demonstrated in primary cultured neurons, melanoma cells, and macrophage cell lines. Cleavage of murine SIRP␣ through an MMP inhibitor-sensitive pathway was first observed in cultured cells engineered to express both SIRP␣ and an active form of Ras (8). In these cells, blocking SIRP␣ proteolysis resulted in inhibited cell migration, cell spreading, and cytoskeletal reorganization. In addition, SIRP␣ was shown to regulate synaptic activity through activation of MMP inhibitor-sensitive prote...

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“…Blocking CD47 decreased macrophage and neutrophil recruitment into reperfused tissues and decreased ROS damage in these models. Consistent with an anti-inflammatory effect of CD47 blockade, administration of CD47-Fc suppressed the lymph node accumulation of SIRPα + dendritic cells, development of systemic and local Th2 responses, and airway inflammation in sensitized and challenged mice [127]. Similarly, administration of soluble SIRP-Fc as a decoy inhibited Langerhans cell migration to lymph nodes and the subsequent contact hypersensitivity upon re-challenge of the mice [128].…”

Section: Preclinical Therapeutic Applicationsmentioning

confidence: 92%

Therapeutic opportunities for targeting the ubiquitous cell surface receptor CD47

Soto-Pantoja

Stein

Rogers

et al. 2012

Expert Opinion on Therapeutic Targets

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Introduction CD47 is a ubiquitously expressed cell surface receptor that serves as a counter-receptor for SIRPα in recognition of self by the innate immune system. Independently, CD47 also functions as an important signaling receptor for regulating cell responses to stress. Areas covered We review the expression, molecular interactions, and pathophysiological functions of CD47 in the cardiovascular and immune systems. CD47 was first identified as a potential tumor marker, and we examine recent evidence that its dysregulation contributes to cancer progression and evasion of anti-tumor immunity. We further discuss therapeutic strategies for enhancing or inhibiting CD47 signaling and applications of such agents in preclinical models of ischemia and ischemia/reperfusion injuries, organ transplantation, pulmonary hypertension, radioprotection, and cancer. Expert opinion Ongoing studies are revealing a central role of CD47 for conveying signals from the extracellular microenvironment that limit cell and tissue survival upon exposure to various types of stress. Based on this key function, therapeutics targeting CD47 or its ligands thrombospondin-1 and SIRPα could have broad applications spanning reconstructive surgery, engineering of tissues and biocompatible surfaces, vascular diseases, diabetes, organ transplantation, radiation injuries, inflammatory diseases, and cancer.

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Targeting SIRP‐α protects from type 2‐driven allergic airway inflammation

Cited by 20 publications

References 36 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

Cleavage of Signal Regulatory Protein α (SIRPα) Enhances Inflammatory Signaling

Therapeutic opportunities for targeting the ubiquitous cell surface receptor CD47

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