title: Cd47-Sirpα interaction and IL-10 constrain inflammation-induced macrophage phagocytosis of healthy self-cells.
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.
authors: 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;
authors: Zhen
authors: Z
authors: Bian
authors: Program of Immunology and Cell Biology, Department of Biology, Center for Diagnostics & Therapeutics, Georgia State University, Atlanta, GA 30302;
authors: Lei
authors: L
authors: Shi
authors: Program of Immunology and Cell Biology, Department of Biology, Center for Diagnostics & Therapeutics, Georgia State University, Atlanta, GA 30302;
authors: Ya-Lan
authors: YL
authors: Guo
authors: Program of Immunology and Cell Biology, Department of Biology, Center for Diagnostics & Therapeutics, Georgia State University, Atlanta, GA 30302;
authors: Zhiyuan
authors: Z
authors: Lv
authors: Program of Immunology and Cell Biology, Department of Biology, Center for Diagnostics & Therapeutics, Georgia State University, Atlanta, GA 30302;
authors: Cong
authors: C
authors: Tang
authors: Program of Immunology and Cell Biology, Department of Biology, Center for Diagnostics & Therapeutics, Georgia State University, Atlanta, GA 30302;
authors: Shuo
authors: S
authors: Niu
authors: Program of Immunology and Cell Biology, Department of Biology, Center for Diagnostics & Therapeutics, Georgia State University, Atlanta, GA 30302;
authors: Alexandra
authors: A
authors: Tremblay
authors: Program of Immunology and Cell Biology, Department of Biology, Center for Diagnostics & Therapeutics, Georgia State University, Atlanta, GA 30302;
authors: Mahathi
authors: M
authors: Venkataramani
authors: Program of Immunology and Cell Biology, Department of Biology, Center for Diagnostics & Therapeutics, Georgia State University, Atlanta, GA 30302;
authors: Courtney
authors: C
authors: Culpepper
authors: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing Advanced Institute for Life Sciences, Nanjing University, Nanjing, Jiangsu 210093, China;
authors: Limin
authors: L
authors: Li
authors: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing Advanced Institute for Life Sciences, Nanjing University, Nanjing, Jiangsu 210093, China;
authors: Zhen
authors: Z
authors: Zhou
authors: Program of Immunology and Cell Biology, Department of Biology, Center for Diagnostics & Therapeutics, Georgia State University, Atlanta, GA 30302;
authors: Ahmed
authors: A
authors: Mansour
authors: Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, Life Science Institute (LSI) Immunology Programme, National University of Singapore, Singapore 117456;
authors: Yongliang
authors: Y
authors: Zhang
authors: Center for Inflammation, Immunity and Infection, Georgia State University, Atlanta, GA 30303;
authors: Andrew
authors: A
authors: Gewirtz
authors: 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.
authors: Koby
authors: K
authors: Kidder
authors: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing Advanced Institute for Life Sciences, Nanjing University, Nanjing, Jiangsu 210093, China;
authors: Ke
authors: K
authors: Zen
authors: 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.
authors: Yuan
authors: Y
authors: Liu
mesh_terms: D000818:Animals; D051928:CD47 Antigen / Q000235:genetics*; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D004705:Endocytosis / Q000235:genetics; D006801:Humans; D007249:Inflammation / Q000235:genetics* / Q000473:pathology; D016753:Interleukin-10 / Q000235:genetics*; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D010587:Phagocytosis / Q000235:genetics; D011493:Protein Kinase C / Q000235:genetics; D011971:Receptors, Immunologic / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics
chemical_list: D051928:CD47 Antigen; C497895:Cd47 protein, mouse; D016207:Cytokines; C501922:Sirpa protein, mouse; D011971:Receptors, Immunologic; D016753:Interleukin-10; D011493:Protein Kinase C
keywords: CD47; SIRPα; cytokine; macrophage; phagocytosis