Cd47-Sirpα interaction and IL-10 constrain inflammation-induced macrophage phagocytosis of healthy self-cells
| Autor: | Ke Zen, Yongliang Zhang, Limin Li, Courtney Culpepper, Ya-Lan Guo, Koby Kidder, Zhen Bian, Zhiyuan Lv, Yuan Liu, Lei Shi, Cong Tang, Alexandra Tremblay, Shuo Niu, Zhen Zhou, Mahathi Venkataramani, Andrew T. Gewirtz, Ahmed Mansour |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Phagocytosis medicine.medical_treatment Inflammation CD47 Antigen Biology 03 medical and health sciences Mice Immune system medicine Macrophage Animals Humans Receptors Immunologic Protein Kinase C Mice Knockout Multidisciplinary CD47 Macrophages Endocytosis Cell biology Interleukin-10 Interleukin 10 030104 developmental biology Cytokine PNAS Plus Immunology Cytokines Tumor necrosis factor alpha medicine.symptom Signal Transduction |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America. 113(37) |
| ISSN: | 1091-6490 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|