Functions and molecular mechanisms of the CD47–SIRPα signalling pathway

Matozaki, Takashi; Murata, Yoji; Okazawa, Hideki; Ohnishi, Hiroshi

doi:10.1016/j.tcb.2008.12.001

Cited by 398 publications

(441 citation statements)

References 84 publications

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“…Last, in mice with disrupted IFN-γ signaling the phagocytosis inhibitory receptor CD172a/Sirpα was increased in microglia, less so in macrophages, and was decreased in DCs. Ligation of macrophage CD172a by CD47 expressed on interacting cells prevents macrophage phagocytosis, whereas impaired CD172a engagement by CD47 promotes macrophage engulfment (57)(58)(59). Along these lines, it has been shown recently that CD47 is expressed by intact myelin and myelinforming oligodendrocytes and may protect them from phagocytosis by microglia and macrophages via interaction with CD172a.…”

Section: Discussionmentioning

confidence: 99%

IFN-γ ameliorates autoimmune encephalomyelitis by limiting myelin lipid peroxidation

Sosa

Murphey

Robinson

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Evidence has suggested both a pathogenic and a protective role for the proinflammatory cytokine IFN-γ in experimental autoimmune encephalomyelitis (EAE). However, the mechanisms underlying the protective role of IFN-γ in EAE have not been fully resolved, particularly in the context of CNS antigen-presenting cells (APCs). In this study we examined the role of IFN-γ in myelin antigen uptake by CNS APCs during EAE. We found that myelin antigen colocalization with APCs was decreased substantially and that EAE was significantly more severe and showed a chronic-progressive course in IFN-γ knockout (IFN-γ −/− ) or IFN-γ receptor knockout (IFN-γR −/− ) mice as compared with WT animals. IFN-γ was a critical regulator of phagocytic/activating receptors on CNS APCs. Importantly, "free" myelin debris and lipid peroxidation activity at CNS lesions was increased in mice lacking IFN-γ signaling. Treatment with N-acetyl-L-cysteine, a potent antioxidant, abolished lipid peroxidation activity and ameliorated EAE in IFN-γ-signalingdeficient mice. Taken together the data suggest a protective role for IFN-γ in EAE by regulating the removal of myelin debris by CNS APCs and thereby limiting the substrate available for the generation of neurotoxic lipid peroxidation products.

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Section: Discussionmentioning

confidence: 99%

IFN-γ ameliorates autoimmune encephalomyelitis by limiting myelin lipid peroxidation

Sosa

Murphey

Robinson

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…The cytoplasmic region of SIRPA has immunoreceptor tyrosine-based inhibitory motifs, and binding cell-surface CD47 with SIRPA on macrophages provokes inhibitory signals through phosphorylation of these inhibitory motifs of SIRPA, 30 preventing their phagocytic activity. [31][32][33] A recent study also showed that transgenic expression of mouse CD47 into CD34 ϩ CD38 Ϫ human fetal liver cells significantly enhanced the human cell engraftment into BALB-RG mice. 34 Based on these data, the binding of NOD-SIRPA with human CD47 might produce signals for mouse macrophages not to engulf human HSCs, which presumably makes the strain permissive for human HSC engraftment.…”

Section: Introductionmentioning

confidence: 96%

Polymorphic Sirpa is the genetic determinant for NOD-based mouse lines to achieve efficient human cell engraftment

Yamauchi

Takenaka

Urata

et al. 2013

Blood

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121

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Key Points• NOD-specific Sirpa polymorphism is the genetic determinant of highly efficient xenograft activity in NOD-based immunodeficient mouse models.Current mouse lines efficient for human cell xenotransplantation are backcrossed into NOD mice to introduce its multiple immunodeficient phenotypes. Our positional genetic study has located the NOD-specific polymorphic Sirpa as a molecule responsible for its high xenograft efficiency: it recognizes human CD47 and the resultant signaling may cause NOD macrophages not to engulf human grafts. In the present study, we established C57BL/6.Rag2 nullIl2rgnull mice harboring NOD-Sirpa (BRGS). BRGS mice engrafted human hematopoiesis with an efficiency that was equal to or even better than that of the NOD.Rag1 nullIl2rgnull strain, one of the best xenograft models. Consequently, BRGS mice are free from other NOD-related abnormalities; for example, they have normalized C5 function that enables the evaluation of complement-dependent cytotoxicity of antibodies against human grafts in the humanized mouse model. Our data show that efficient human cell engraftment found in NOD-based models is mounted solely by their polymorphic Sirpa. The simplified BRGS line should be very useful in future studies of human stem cell biology. (Blood. 2013;121(8):1316-1325) IntroductionImmunodeficient mice are widely used to reconstitute human hematopoiesis by xenotransplantation of hematopoietic stem cells (HSCs). 1,2 This "humanized" mouse model provides a powerful tool with which to evaluate the biologic properties of human HSCs and progenitors in vivo. 3,4 Such xenotransplantation systems have also been used to study human cancer stem cells. [5][6][7][8] Elimination of the lymphoid system is the first step to achieving reconstitution of human hematopoiesis. To deplete T and B cells, the scid mutation in the Prkdc gene [9][10][11] or disruption of the recombination activating gene 1 or 2 (Rag1 and Rag2) 12,13 has been introduced into various mouse strains. In addition, to deplete natural killer (NK) cells or their functions, the IL-2 receptor common ␥ chain subunit (Il2rg) [14][15][16] or beta-2-microglobulin (B2m) [17][18][19] is disrupted.However, depletion of lymphoid cells is not sufficient and it has been shown empirically that additional strain-specific factors modulate human hematopoietic engraftment in the xenotransplantation setting. For example, within the SCID strain, the SCID with the NOD background was the gold standard for the xenotransplantation assay based on its high efficiency. 11 In fact, recent studies have shown that among the lymphoid-depleted mouse strains, the NOD-scid Il2rg null (NSG/NOG) 14,15 and NOD.Rag1 null Il2rg null (NOD-RG) 20 strains are the most efficient; the BALB/c.Rag2 null Il2rg null (BALB-RG) strain is the next efficient 21,22 ; and the C57BL/6 strains with scid, 23 Rag2 null , Rag2 null B2m null , Rag2 null Prf null , 24 or Rag2 null Jak3 null25 mutations are unable to reconstitute human hematopoiesis. The NOD strain has multiple immune deficiencies, ...

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“…One essential mechanism that prevents macrophages from doing so is CD47-signal regulatory protein α (SIRPα) interaction-mediated inhibition (1)(2)(3)(4). In this mechanism, CD47, a broadly expressed cell surface protein that acts as a marker of self, along with SIRPα, the counter receptor of CD47 expressed on macrophages and other phagocytic leukocytes, serve as an inhibitory signaling regulator (5-7).…”

mentioning

confidence: 99%

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

Bian

Shi

Guo

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

119

121

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Rapid clearance of adoptively transferred Cd47-null (Cd47−/−) cells in congeneic WT mice suggests a critical self-recognition mechanism, in which CD47 is the ubiquitous marker of self, and its interaction with macrophage signal regulatory protein α (SIRPα) triggers inhibitory signaling through SIRPα cytoplasmic immunoreceptor tyrosine-based inhibition motifs and tyrosine phosphatase SHP-1/2. However, instead of displaying self-destruction phenotypes, Cd47−/− mice manifest no, or only mild, macrophage phagocytosis toward self-cells except under the nonobese diabetic background. Studying our recently established Sirpα-KO (Sirpα−/−) mice, as well as Cd47−/− mice, we reveal additional activation and inhibitory mechanisms besides the CD47-SIRPα axis dominantly controlling macrophage behavior. Sirpα−/− mice and Cd47−/− mice, although being normally healthy, develop severe anemia and splenomegaly under chronic colitis, peritonitis, cytokine treatments, and CFA-/LPS-induced inflammation, owing to splenic macrophages phagocytizing self-red blood cells. Ex vivo phagocytosis assays confirmed general inactivity of macrophages from Sirpα−/− or Cd47−/− mice toward healthy self-cells, whereas they aggressively attack toward bacteria, zymosan, apoptotic, and immune complex-bound cells; however, treating these macrophages with IL-17, LPS, IL-6, IL-1β, and TNFα, but not IFNγ, dramatically initiates potent phagocytosis toward self-cells, for which only the Cd47-Sirpα interaction restrains. Even for macrophages from WT mice, phagocytosis toward Cd47−/− cells does not occur without phagocytic activation. Mechanistic studies suggest a PKC-Syk–mediated signaling pathway, to which IL-10 conversely inhibits, is required for activating macrophage self-targeting, followed by phagocytosis independent of calreticulin. Moreover, we identified spleen red pulp to be one specific tissue that provides stimuli constantly activating macrophage phagocytosis albeit lacking in Cd47−/− or Sirpα−/− mice.

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Functions and molecular mechanisms of the CD47–SIRPα signalling pathway

Cited by 398 publications

References 84 publications

IFN-γ ameliorates autoimmune encephalomyelitis by limiting myelin lipid peroxidation

IFN-γ ameliorates autoimmune encephalomyelitis by limiting myelin lipid peroxidation

Polymorphic Sirpa is the genetic determinant for NOD-based mouse lines to achieve efficient human cell engraftment

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

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