Cd47-Sirpα interaction and IL-10 constrain inflammation-induced macrophage phagocytosis of healthy self-cells

Bian, Zhen; Shi, Lei; Guo, Ya-Lan; Lv, Zhiyuan; Tang, Cong; Niu, Shuo; Tremblay, Alexandra; Venkataramani, Mahathi; Culpepper, Courtney; Liu, Limin; Zhou, Zhen; Mansour, Ahmed; Zhang, Yongliang; Gewirtz, Andrew T.; Kidder, Koby; Zen, Ke; Liu, Yuan

doi:10.1073/pnas.1521069113

Cited by 121 publications

(139 citation statements)

References 66 publications

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“…Yet, depending u n o p s a n t i -R h D p a t i e n t I p a t i e n t I I p a t i e n t I I I p a t i e n t I V p a t i e n t V p a t i e n t V I a n t i -G P A Figure 7D). Although Bian et al showed this same effect in vivo in mice for multiple stimuli, 34 in our assay other stimuli did not have this effect. Overall, our data demonstrate that various inflammatory mediators can lower the threshold for phagocytosis of IgG-opsonized RBCs by neutrophils.…”

Section: Neutrophil Priming Enhances Erythrophagocytosissupporting

confidence: 53%

Human and murine splenic neutrophils are potent phagocytes of IgG-opsonized red blood cells

et al. 2017

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Key Points• In steady state, where no IgGs against RBCs are present, macrophages are the primary phagocytes of RBCs.• In conditions where RBCs are IgGopsonized, neutrophils can have a major effect on RBC clearance.Red blood cell (RBC) clearance is known to occur primarily in the spleen, and is presumed to be executed by red pulp macrophages. Erythrophagocytosis in the spleen takes place as part of the homeostatic turnover of RBCs to remove old RBCs. It can be strongly promoted by immunoglobulin G (IgG) opsonization of RBCs, a condition that can occur as a consequence of autoantibody or alloantibody formation. The purpose of our study was to investigate which phagocytes are involved in IgG-mediated RBC clearance in the human spleen. We developed a highly specific in vitro assay to monitor RBC phagocytosis in total human splenocytes. Surprisingly, we have found that whereas homeostatic clearance of RBCs is primarily a task for splenic macrophages, neutrophils and, to a lesser extent, also monocytes can be a major factor in clearance of IgG-opsonized RBCs. Erythrophagocytosis by neutrophils is strongly dependent on the degree of opsonization of the RBCs. Additionally, the process is enhanced after blocking the "do not eat me" signal CD47 on the opsonized RBCs, which binds signal regulatory protein a, a myeloid inhibitory receptor that restricts phagocytosis. Moreover, RBCs isolated from autoimmune hemolytic anemia patients, opsonized by auto-IgGs, were shown to be readily phagocytosed by neutrophils. Finally, priming of neutrophils by inflammatory mediators such as tumor necrosis factor a and lipopolysaccharide further increases the magnitude of erythrophagocytosis. Collectively, our data suggest that neutrophils contribute significantly to the phagocytosis of antibody-opsonized RBCs, especially under inflammatory conditions. This indicates a hereto unanticipated contribution of neutrophils in RBC phagocytosis, especially under pathological conditions such as alloimmunization or autoimmunization.

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Section: Neutrophil Priming Enhances Erythrophagocytosissupporting

confidence: 53%

Human and murine splenic neutrophils are potent phagocytes of IgG-opsonized red blood cells

et al. 2017

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“…In nonhuman primates, therapeutic dosing of CD47-blocking agents can be achieved while limiting side effects (11, 30). IL10 appears to prevent macrophages from attacking healthy cells when the CD47/SIRPα interaction is disrupted (55); other factors that regulate the response to treatment likely depend on a balance between pro-phagocytic and other inhibitory signals, and the identification of these signals remains an active area of investigation.…”

Section: Discussionmentioning

confidence: 99%

Eradication of Canine Diffuse Large B-Cell Lymphoma in a Murine Xenograft Model with CD47 Blockade and Anti-CD20

Weiskopf

Anderson

Ito

et al. 2016

Cancer Immunology Research

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Cancer immunotherapies hold much promise, but their potential in veterinary settings has not yet been fully appreciated. Canine lymphomas are among the most common tumors of dogs and bear remarkable similarity to human disease. In this study, we examined the combination of CD47 blockade with anti-CD20 passive immunotherapy for canine lymphoma. The CD47/SIRPα axis is an immune checkpoint that regulates macrophage activation. In humans, CD47 is expressed on cancer cells and enables evasion from phagocytosis. CD47-blocking therapies are now under investigation in clinical trials for a variety of human cancers. We found the canine CD47/SIRPα axis to be conserved biochemically and functionally. We identified high-affinity SIRPα variants that antagonize canine CD47 and stimulate phagocytosis of canine cancer cells in vitro. When tested as Fc fusion proteins, these therapeutic agents exhibited single-agent efficacy in a mouse xenograft model of canine lymphoma. Since robust synergy between CD47 blockade and tumor-specific antibodies has been demonstrated for human cancer, we evaluated the combination of CD47-blockade with 1E4-cIgGB, a canine-specific antibody to CD20. 1E4-cIgGB could elicit a therapeutic response against canine lymphoma in vivo as a single agent. However, augmented responses were observed when combined with CD47-blocking therapies, resulting in synergy in vitro and in vivo and eliciting cures in 100% of mice bearing canine lymphoma. Our findings support further testing of CD47-blocking therapies alone and in combination with CD20 antibodies in the veterinary setting.

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“…Consistent with this notion, CD47 −/− cells are cleared rapidly when they are adoptively transferred to the congeneic wild-type mice [15]. However, it was recently shown that CD47-SIRPα axis, while crucial, represents just one mechanism that controls phagocytic behavior [16]. Indeed, CD47 −/− mice do not manifest significant self-destruction phenotype unless they are in inflammatory conditions.…”

Section: Introductionmentioning

confidence: 96%

“…Indeed, CD47 −/− mice do not manifest significant self-destruction phenotype unless they are in inflammatory conditions. Inflammatory cytokines stimulate protein kinase C-spleen tyrosine kinase (PKC-Syk) signaling pathway (which IL-10 negatively regulates), which then activates macrophage to target self cells [16]. Combined, these findings suggest a potential mechanism for anemia of chronic disease and that rhesus (Rh)-null individuals, who have <25% of normal CD47 levels, may be particularly vulnerable to anemia under inflammatory conditions and infections [17].…”

Section: Introductionmentioning

confidence: 99%

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Is CD47 an innate immune checkpoint for tumor evasion?

et al. 2017

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Cluster of differentiation 47 (CD47) (also known as integrin-associated protein) is a ubiquitously expressed glycoprotein of the immunoglobulin superfamily that plays a critical role in self-recognition. Various solid and hematologic cancers exploit CD47 expression in order to evade immunological eradication, and its overexpression is clinically correlated with poor prognoses. One essential mechanism behind CD47-mediated immune evasion is that it can interact with signal regulatory protein-alpha (SIRPα) expressed on myeloid cells, causing phosphorylation of the SIRPα cytoplasmic immunoreceptor tyrosine-based inhibition motifs and recruitment of Src homology 2 domain-containing tyrosine phosphatases to ultimately result in delivering an anti-phagocytic—“don’t eat me”—signal. Given its essential role as a negative checkpoint for innate immunity and subsequent adaptive immunity, CD47-SIRPα axis has been explored as a new target for cancer immunotherapy and its disruption has demonstrated great therapeutic promise. Indeed, CD47 blocking antibodies have been found to decrease primary tumor size and/or metastasis in various pre-clinical models. In this review, we highlight the various functions of CD47, discuss anti-tumor responses generated by both the innate and adaptive immune systems as a consequence of administering anti-CD47 blocking antibody, and finally elaborate on the clinical potential of CD47 blockade. We argue that CD47 is a checkpoint molecule for both innate and adaptive immunity for tumor evasion and is thus a promising target for cancer immunotherapy.

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Cd47-Sirpα interaction and IL-10 constrain inflammation-induced macrophage phagocytosis of healthy self-cells

Cited by 121 publications

References 66 publications

Human and murine splenic neutrophils are potent phagocytes of IgG-opsonized red blood cells

Human and murine splenic neutrophils are potent phagocytes of IgG-opsonized red blood cells

Eradication of Canine Diffuse Large B-Cell Lymphoma in a Murine Xenograft Model with CD47 Blockade and Anti-CD20

Is CD47 an innate immune checkpoint for tumor evasion?

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