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Proc Natl Acad Sci U S A. 2016 Sep 13;113(37):E5434-43. doi: 10.1073/pnas.1521069113. Epub 2016 Aug 30.

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

Author information

1
Program of Immunology and Cell Biology, Department of Biology, Center for Diagnostics & Therapeutics, Georgia State University, Atlanta, GA 30302; State Key Laboratory of Pharmaceutical Biotechnology, Nanjing Advanced Institute for Life Sciences, Nanjing University, Nanjing, Jiangsu 210093, China;
2
Program of Immunology and Cell Biology, Department of Biology, Center for Diagnostics & Therapeutics, Georgia State University, Atlanta, GA 30302;
3
State Key Laboratory of Pharmaceutical Biotechnology, Nanjing Advanced Institute for Life Sciences, Nanjing University, Nanjing, Jiangsu 210093, China;
4
Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, Life Science Institute (LSI) Immunology Programme, National University of Singapore, Singapore 117456;
5
Center for Inflammation, Immunity and Infection, Georgia State University, Atlanta, GA 30303;
6
Program of Immunology and Cell Biology, Department of Biology, Center for Diagnostics & Therapeutics, Georgia State University, Atlanta, GA 30302; Department of Cell Biology, Rutgers University, New Brunswick, NJ 08901.
7
Program of Immunology and Cell Biology, Department of Biology, Center for Diagnostics & Therapeutics, Georgia State University, Atlanta, GA 30302; Center for Inflammation, Immunity and Infection, Georgia State University, Atlanta, GA 30303; yliu@gsu.edu.

Abstract

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.

KEYWORDS:

CD47; SIRPα; cytokine; macrophage; phagocytosis

PMID:
27578867
PMCID:
PMC5027463
DOI:
10.1073/pnas.1521069113
[Indexed for MEDLINE]
Free PMC Article

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