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Macrophages show higher levels of engulfment after disruption of cis interactions between CD47 and the checkpoint receptor SIRP?.

ABSTRACT: The macrophage checkpoint receptor SIRP? signals against phagocytosis by binding CD47 expressed on all cells - including macrophages. Here, we found that inhibiting cis interactions between SIRP? and CD47 on the same macrophage increased engulfment ('eating') by approximately the same level as inhibiting trans interactions. Antibody blockade of CD47, as pursued in clinical trials against cancer, was applied separately to human-derived macrophages and to red blood cell (RBC) targets for phagocytosis, and both scenarios produced surprisingly similar increases in RBC engulfment. Blockade of both macrophages and targets resulted in hyper-phagocytosis, and knockdown of macrophage-CD47 likewise increased engulfment of 'foreign' cells and particles, decreased the baseline inhibitory signaling of SIRP?, and linearly increased binding of soluble CD47 in trans, consistent with cis-trans competition. Many cell types express both SIRP? and CD47, including mouse melanoma B16 cells, and CRISPR-mediated deletions modulate B16 phagocytosis, consistent with cis-trans competition. Additionally, soluble SIRP? binding to human CD47 displayed on Chinese hamster ovary (CHO) cells was suppressed by SIRP? co-display, and atomistic computations confirm SIRP? bends and binds CD47 in cis Safety and efficacy profiles for CD47-SIRP? blockade might therefore reflect a disruption of both cis and trans interactions.

SUBMITTER: Hayes BH

PROVIDER: S-EPMC7064788 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Macrophages show higher levels of engulfment after disruption of cis interactions between CD47 and the checkpoint receptor SIRPα.

Hayes Brandon H BH Tsai Richard K RK Dooling Lawrence J LJ Kadu Siddhant S Lee Justine Y JY Pantano Diego D Rodriguez Pia L PL Subramanian Shyamsundar S Shin Jae-Won JW Discher Dennis E DE

Journal of cell science 20200306 5

The macrophage checkpoint receptor SIRPα signals against phagocytosis by binding CD47 expressed on all cells - including macrophages. Here, we found that inhibiting cis interactions between SIRPα and CD47 on the same macrophage increased engulfment ('eating') by approximately the same level as inhibiting trans interactions. Antibody blockade of CD47, as pursued in clinical trials against cancer, was applied separately to human-derived macrophages and to red blood cell (RBC) targets ...[more]

PMID: 31964705

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Project description: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 ? (SIRP?) triggers inhibitory signaling through SIRP? 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 Sirp?-KO (Sirp?(-/-)) mice, as well as Cd47(-/-) mice, we reveal additional activation and inhibitory mechanisms besides the CD47-SIRP? axis dominantly controlling macrophage behavior. Sirp?(-/-) 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 Sirp?(-/-) 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-1?, and TNF?, but not IFN?, dramatically initiates potent phagocytosis toward self-cells, for which only the Cd47-Sirp? 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 Sirp?(-/-) mice.

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Macrophages show higher levels of engulfment after disruption of cis interactions between CD47 and the checkpoint receptor SIRP?.

Publications

Macrophages show higher levels of engulfment after disruption of <i>cis</i> interactions between CD47 and the checkpoint receptor SIRPα.

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