Attenuation of phagocytosis of xenogeneic cells by manipulating CD47

Self Cite

112

Macrophages recognize CD47 as a marker of ''self'' and phagocytose CD47 null hematopoietic cells. Using CD47 chimera models, here, we show that the phagocytic activity of macrophages against CD47 null hematopoietic cells is conferred by CD47 expression on nonhematopoietic cells, and this ''education'' process is hematopoietic cell-independent. Macrophages in the chimeras where nonhematopoietic cells express CD47 phagocytose CD47 null cells, whereas those in the chimeras lacking CD47 on nonhematopoietic cells are tolerant to CD47 null cells. However, macrophages in the latter chimeras retain phagocytic activity against CD47 null RBCs, demonstrating a split macrophage tolerance to CD47 null hematopoietic cells. The findings highlight the potential importance of nonhematopoietic cells in the regulation of macrophage function, and suggest a previously uncharacterized mechanism of macrophage tolerance.chimera ͉ phagocytosis ͉ signaling regulatory protein-␣

Section: Discussionmentioning

confidence: 66%

Lack of CD47 on nonhematopoietic cells induces split macrophage tolerance to CD47^nullcells

Wang

Madariaga²,

Wang³

et al. 2007

Self Cite

112

“…In addition, we have recently demonstrated that pig CD47 does not interact with mouse SIRP␣ (25). However, it remained to be elucidated whether pig CD47-human SIRP␣ interactions could deliver a signal inhibiting engulfment or not.…”

Section: Discussionmentioning

confidence: 99%

Role for CD47-SIRPα signaling in xenograft rejection by macrophages

Ide

Wang

Tahara

et al. 2007

Self Cite

277

256

We have previously proven that human macrophages can phagocytose porcine cells even in the absence of Ab or complement opsonization, indicating that macrophages present a pivotal immunological obstacle to xenotransplantation. A recent report indicates that the signal regulatory protein (SIRP)␣ is a critical immune inhibitory receptor on macrophages, and its interaction with CD47, a ligand for SIRP␣, prevents autologous phagocytosis. Considering the limited compatibility (73%) in amino acid sequences between pig and human CD47, we hypothesized that the interspecies incompatibility of CD47 may contribute to the rejection of xenogeneic cells by macrophages. In the present study, we have demonstrated that porcine CD47 does not induce SIRP␣ tyrosine phosphorylation in human macrophage-like cell line, and soluble human CD47-Fc fusion protein inhibits the phagocytic activity of human macrophages toward porcine cells. In addition, we have verified that manipulation of porcine cells for expression of human CD47 radically reduces the susceptibility of the cells to phagocytosis by human macrophages. These results indicate that the interspecies incompatibility of CD47 significantly contributes to the rejection of xenogeneic cells by macrophages. Genetic induction of human CD47 on porcine cells could provide inhibitory signaling to SIRP␣ on human macrophages, providing a novel approach to preventing macrophage-mediated xenograft rejection.xenotransplantation ͉ phagocytosis ͉ reticuloendothelial system

“…Conversely, the lack of a compatible CD47 to ligate the recipient SIRPα is considered to be associated with tissue rejection in xenotransplantation (22)(23)(24)(25).…”

Section: Significancementioning

confidence: 99%

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

Bian

Shi

Guo

et al. 2016

119

121

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.