Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Sirpa

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101830

Synonyms

Historical Background, Structure, and Its Ligands

Signal regulatory protein alpha (SIRPα) was initially cloned as a substrate for Src homology region 2 (SH2) domain-containing phosphatase-1 (SHP-1) (Ptpn6) and SHP-2 (Ptpn11). SHP-1 and SHP-2 are cytoplasmic-type protein tyrosine phosphatases and SIRPα was initially termed SHPS-1 (SHP substrate-1) (reviewed in Matozaki et al. 2009; Barclay and van den Berg 2014). SIRPα was also named as brain immunoglobulin (Ig)-like molecule with tyrosine-based activation motifs (BIT), which was a highly phosphorylated glycoprotein in the brain, as well as macrophage fusion receptor (MFR) and MyD-1. SIRPα belongs to SIRP family members, and other two SIRP family members, namely SIRPβ1 and SIRPγ, have a similar structure of SIRPα in their extracellular regions but have different cytoplasmic regions from SIRPα (Matozaki et al. 2009; Barclay and van den Berg 2014).

The extracellular region of SIRPα consists of three immunoglobulin-like domains (Fig. 1). The cytoplasmic region of SIRPα comprises tyrosine residues with immunoreceptor tyrosine-based inhibitory motifs (ITIMs), which activate SHP-1 and SHP-2, mediating the specific biological function of SIRPα (Matozaki et al. 2009). The intracellular region of SIRPα also binds the adaptor molecules Src kinase-associated phosphoprotein 2 (SKAP2) and Fyn-binding protein/SLP-76-associated phosphoprotein of 130 kDa (FYB/SLAP-130), as well as the tyrosine kinase PYK2 (Timms et al. 1999). In addition, the extracellular region of SIRPα physiologically binds CD47, a member of the Ig superfamily protein (Fig. 1). The extracellular region of SIRPα also binds the lung surfactant proteins SP-A and SP-D, which are thought to play protective roles against bacterial infections (Gardai et al. 2003). SIRPα is especially expressed on neurons, pancreatic β cells, and myeloid lineage cells such as macrophages, dendritic cells, and neutrophils. Other type of cells (e.g., fibroblasts and endothelial cells) also expresses SIRPα, but the expression level of SIRPα in such type of cells is lower than that of the former cells. By contrast, CD47 is expressed in most cell types.
Sirpa, Fig. 1

Schematic structures of SIRPα and CD47. SIRPα is a transmembrane protein comprising three Ig-like domains (one IgV-like and two IgC1-like domains) in its extracellular region and four phosphorylation sites in its C-terminal cytoplasmic region. The tyrosine-phosphorylated sites of SIRPα bind to the protein tyrosine phosphatases, SHP-1 and SHP-2, and subsequently activate these phosphatases. CD47, a ligand for SIRPα, is also a member of the Ig superfamily, carrying an IgV-like extracellular domain, five membrane-spanning segments, and a short cytoplasmic tail. The N-terminal IgV-like domain of SIRPα trans-interacts with the IgV-like domain of CD47, which could mediate intercellular signaling in a bidirectional manner

The N-terminal IgV-like domain of SIRPα is highly polymorphic in both human and mouse. These polymorphisms of SIRPα are thought to affect its interaction with CD47. Indeed, the polymorphic variants of human SIRPα, as well as mouse SIRPα, showed different phagocytic activity toward CD47-expressing target cells (Nuvolone et al. 2013; Rodriguez et al. 2013). Thus, SIRPα polymorphisms might be crucial for regulation of phagocytosis by interaction with CD47, nevertheless crystal structure analysis of the N-terminal IgV-like domain of SIRPα suggested that the polymorphisms in SIRPα are unlikely to affect CD47 binding in humans.

SIRPα in Central Nervous System

SIRPα is expressed throughout the brain, especially abundant in the hippocampus and cerebellum as well as in the retina (Ohnishi et al. 2005). A detailed analysis of primary-cultured neurons revealed that SIRPα presents on both axons and dendrites, whereas the expression of CD47 was largely restricted to dendrites (Ohnishi et al. 2005). In addition, forced expression of CD47 on primary-cultured neurons promoted filopodia formation and spine formation of neurons (Murata et al. 2006), suggesting that the SIRPα-CD47 interaction between neighboring neurons plays an important role in neural network formation. Moreover, SIRPα is also expressed on microglia, which is important for demyelination of axons. Given that CD47 is expressed on myelin, the interaction of SIRPα on microglia with CD47 on myelin is thought to play a protective role in C3bi-dependent myelin phagocytosis (Gitik et al. 2011).

Several studies demonstrated that the BDNF receptor TrkB as well as Src family kinases (SFKs) mediate the tyrosine phosphorylation of SIRPα, which subsequently activate SHP-2 (Matozaki et al. 2009). Furthermore, the forced swimming test (an in vivo experimental model for stress-induced responses) as well as exposure of mice to cold stress revealed robust tyrosine phosphorylation of SIRPα, which was followed by activation of SHP-2 (Maruyama et al. 2012; Ohnishi et al. 2010). Thus, the function of SIRPα in the brain may be closely related to behavioral immobility. A recent study further documented that SIRPα also participated in the oxidative stress and the pathology of ischemic stroke in the brain. The size of cerebral ischemia was attenuated, and the neural damages were inhibited in SIRPα-deficient mice after cerebral artery occlusion (Wang et al. 2012).

SIRPα Inhibits Phagocytic Activity of Macrophages

Macrophages are “professional” phagocytes, which play important roles in the preservation of tissue integrity and clearance of old cells or apoptotic cells. As mentioned above, SIRPα is preferentially expressed on macrophages. Ligation of CD47 on target cells with SIRPα on macrophages plays crucial roles in the regulation of phagocytosis by macrophages of target cells (Fig. 2). For instance, infusion of CD47-deficient RBCs into wild-type mice induced rapid clearance of CD47-deficient RBCs by host wild-type macrophages (Oldenborg et al. 2000). Similarly, the clearance of IgG-opsonized RBCs obtained from wild-type mice was immediately eliminated by host macrophages in SIRPα-deficient mice (Ishikawa-Sekigami et al. 2006). Such elimination of target cells by macrophages has shown to be dependent on SHP-1(Okazawa et al. 2005) and is also implicated in the clearance of circulating platelets or lymphocytes by macrophages.
Sirpa, Fig. 2

Regulation of phagocytosis by the SIRPα-CD47 signaling. Ligation of SIRPα on macrophages by CD47 on target cells (e.g., red blood cells and platelets) promotes tyrosine phosphorylation of SIRPα, which in turn activates tyrosine phosphatase SHP-1, and subsequently inhibits phagocytosis of target cells by macrophages

Moreover, recent studies indicated that rejection of xenograft donor cells is critically regulated by SIRPα expressed on host macrophages in the generation of humanized mouse models for studying human Immunology and hematology. Of interest is that the nonobese diabetic (NOD) mouse strain expresses a polymorphic variant of SIRPα, which can bind human CD47 with a high affinity. The binding is thought to inhibit the elimination of human donor cells by NOD-derived macrophages (Takenaka et al. 2007). Breeding of the NOD SIRPα gene onto the immunodeficient animals, as well as introduction of a bacterial artificial chromosome encoding human SIRPα into the immunodeficient animals, showed significantly improved multilineage development of human cells after transplantation of human hematopoietic stem and progenitor cells into these mice (Strowig et al. 2011; Yamauchi et al. 2013). Taken together, the interaction between CD47 on donor cells and SIRPα on recipient macrophages is important for success in xenotransplantation.

SIRPα on Phagocytes Acts as a Potential Therapeutic Target Against Tumors

Interaction of CD47 on tumor cells with SIRPα on macrophages has recently appeared to prevent tumor cells from FcγR-mediated elimination by macrophages (Fig. 3a). It has been reported that the expression of CD47 was increased in multiple human tumors (e.g., acute myeloid leukemia [AML], non-Hodgkin’s lymphoma [NHL], ovarian cancer, and breast cancer) compared to normal tissue or cells (Chao et al. 2012; Willingham et al. 2012). Furthermore, such predominant expression of CD47 on tumor cells was correlated with poor clinical outcomes in patients with AML, NHL, ovarian cancer, and glioma (Chao et al. 2012; Willingham et al. 2012). Thus, the increased expression of CD47 on tumor cells has been considered to be a prediction marker as well as a molecular target for cancer immunotherapy. Indeed, various studies have shown the effect of the anti-CD47 antibodies or SIRPα-Fc fusion proteins on the elimination of tumor cells both in vitro and in vivo using xenograft tumor model (Chao et al. 2012). Thus, the blockade of the interaction between CD47 and SIRPα can be effective treatment for a variety of tumors. Dendritic cells also participate in antitumor effect by uptaking tumor cells, processing and presenting tumor cells into T cells to induce adaptive immune responses against tumors (Liu et al. 2015). Patients with AML and solid tumors are now being recruited for phase I/II clinical trials of anti-CD47 antibody therapy (Hu5F9-G4) (ClinicalTrials.gov identifiers: NCT02678338 and NCT02216409).
Sirpa, Fig. 3

Regulation of tumor cell elimination by macrophages through the SIRPα-CD47 interaction. (a) Treatment with therapeutic monoclonal antibodies specific for tumor antigens (tumor antigen-specific antibody) could induce Fcγ receptor (FcγR)-dependent phagocytosis of tumor cells. Interaction of CD47 (on tumor cells) with SIRPα (on macrophages) prevents the elimination of tumor cells by macrophages. (b) The blockage of the SIRPα-CD47 interaction by the anti-SIRPα antibody could enhance the elimination of tumor cells by macrophages. In some tumors, the expression of SIRPα is markedly increased. Treatment with the anti-SIRPα antibody could induce FcγR-dependent phagocytosis of SIRPα-expressing tumor cells, in addition to the blocking effect of the anti-SIRPα antibody on the elimination of tumor cells by macrophages

Furthermore, a recent study has revealed that the expression of SIRPα is remarkably increased in some tumors including renal cell carcinoma, malignant melanoma, and acute myelomonocytic leukemia compared with normal cells. Thus, in addition to anti-CD47 antibody therapy, an anti-SIRPα antibody therapy that prevents the SIRPα-CD47 interaction could be used for a potential cancer immunotherapy. The treatment of SIRPα expressing tumors with the blocking antibody against SIRPα alone indeed revealed to eliminate tumor cells by macrophages (Yanagita et al. 2017) (Fig. 3b). This therapeutic effect of the anti-SIRPα antibody could be mediated by dual mechanisms: direct induction of antibody-dependent cellular phagocytosis of tumor cells by macrophages and blockade of CD47-SIRPα signaling that negatively regulates such phagocytosis. Moreover, the anti-SIRPα antibody therapy also promotes the effect of anti-CD20 antibody (Rituximab) or anti-programmed cell death 1 (PD-1) antibody on tumor progression in mice inoculated with tumor cells, suggesting that anti-SIRPα antibody therapy has a therapeutic potential for a broad range of cancers (Yanagita et al. 2017).

SIRPα Regulates Homeostasis of Dendritic Cells and T Cells in the Secondary Lymphoid Organs

DCs are professional antigen presenting cells, which are important for initiation of the immune responses during inflammation. DCs are also crucial for induction of central and peripheral tolerance, both of which repress activation of self-reactive T cells. DCs are a heterogeneous population and largely consist of two major subsets, namely plasmacytoid DCs and conventional DCs (cDCs). cDCs are mainly involved in antigen presentation and differentiation of T helper (Th) cells through production of specific cytokines during inflammation. cDCs can be further classified into type 1 (cDC1) and type 2 (cDC2) cDC subsets by the expression of the chemokine receptor XCR1 and SIRPα, respectively. The cDC1 subset is essential for cross-presentation of exogenous antigens and induction of antigen-specific cytotoxic T cells, whereas the cDC2 subset is implicated in the differentiation of Th cells, particularly of Th17 cells. Studies using SIRPα-deficient animals clearly demonstrated that SIRPα on cDCs was essential for the homeostatic regulation of the cDC2 subset in secondary lymphoid organs (SLOs) (Saito et al. 2010), as well as in the small intestine (Kanazawa et al. 2010). In addition, SIRPα, which was also expressed in Langerhans cells (LCs) in the skin epidermis, was shown to regulate homeostasis of LCs. Of note, a decrease of the cDC2 subset was also observed in CD47-deficient mice, suggesting that the interaction between SIRPα and CD47 is crucial for the homeostasis of these cDC subsets. The mechanism underlying the homeostatic regulation of cDCs by the CD47-SIRPα interaction has remained obscure, but recent work suggested that chronic activation of the cDC2 subset by CD47-deficient RBCs was involved in such a reduction of cDC2 subset, at least in the spleen (Yi et al. 2015) (Fig. 4).
Sirpa, Fig. 4

Regulation of cDC homeostasis by the SIRPα-CD47 interaction. Interaction of SIRPα on the type 2 conventional dendritic cells (cDC2) with CD47 on nonhematopoietic cells (such as stromal cells) regulates homeostasis of cDC2 in secondary lymphoid organs. In addition, CD47 on other hematopoietic cells (such as red blood cells) might be involved in the activation and homeostasis of the cDC2 subset in secondary lymphoid organs, particularly in the spleen

Interaction of CD47 with SIRPα is also thought to regulate homeostasis of T cells and stromal cells in the T cell zone, namely fibroblastic reticular cells (FRCs), in the spleen. FRCs produce homeostatic chemokines such as CCL19 and CCL21, both are crucial for the attraction and retention of T cells. FRCs also produce interleukin (IL)-7, which supports the survival of T cells. The amount of T cells and FRCs, as well as production of these homeostatic chemokines and cytokine, was significantly reduced in the spleen of both SIRPα- and CD47-deficient mice (Sato-Hashimoto et al. 2011). Studies from bone marrow chimeras indicated that hematopoietic SIRPα, likely on DCs or macrophages, might regulate the homeostasis of T cells and FRCs in SLOs (Sato-Hashimoto et al. 2011).

SIRPα Regulates Inflammation and Autoimmunity

The transmigration of neutrophils or monocytes from the circulation into tissue parenchyma is crucial for the development of inflammation. Previous in vitro studies revealed that the interaction between SIRPα on neutrophils or monocytes and CD47 on endothelial cells likely promotes the extravasation of these leukocytes during infection (Barclay and van den Berg 2014). Moreover, antibodies against SIRPα or CD47-Ig fusion protein inhibited in vitro migration of neutrophils, monocytes, or melanoma cells (Matozaki et al. 2009). Besides migration and extravasation of neutrophils or macrophages, SIRPα was also reported to be a negative regulator of the oxidative microbial killing by these cells. Inhibition of SIRPα indeed promoted NADPH oxidase production by neutrophils or macrophages, and CD47 was also required for such production (van Beek et al. 2012).

On the other hand, studies from SIRPα-deficient animals indicated that SIRPα was essential for the induction of Th17- or Th1-cell induced autoimmune diseases, such as experimental autoimmune encephalomyelitis (EAE), collagen-induced arthritis (CIA), 2,4-dinitro-1-fluorobenzene-induced contact hypersensitivity (CHS), and IL-10 deficiency-induced colitis (reviewed in Murata et al. 2014). In these models, the production of IL-17 or interferon-γ by Th cells against the disease-specific antigens was remarkably impaired in SIRPα-deficient mice. Of note, CD47-deficient mice were also shown to be resistant to EAE (Han et al. 2012), CHS, and colitis models, and the interaction between SIRPα and CD47 is thus likely required for the development of Th17- or Th1-cell induced autoimmune diseases. However, it remains an open question why SIRPα is essential for the development of autoimmunity. Given that DCs are thought to be crucial for the generation of autoreactive Th17- or Th1- cells, the reduced susceptibility to the development of autoimmune diseases in SIRPα-deficient mice is likely attributable to the impairment of DC functions.

Summary

In summary, SIRPα is important for the homeostatic regulation of myeloid cell functions, in particular, the phagocytic activity of macrophages and homeostasis of DCs in the immune system. SIRPα is also abundant in synapse-rich areas in the brain and the SIRPα-CD47 signaling regulates neural networks. Moreover, there is the possibility that SIRPα polymorphism is a key determinant of these functions in the immune system as well as in the brain. Targeting SIRPα (e.g. antibodies or recombinant proteins) might provide a novel therapeutic strategy against hematopoietic disorders, autoimmune disorders, organ transplantation, as well as cancer immunotherapy.

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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Division of Molecular and Cellular Signaling, Department of Biochemistry and Molecular BiologyKobe University Graduate School of MedicineKobeJapan